Glial cell cytoplasmic inclusions in SCA2 do not express alpha-synuclein.
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Adult↗
Biomedical subjects
Isidro Ferrer
Publications and source records attributed to Isidro Ferrer.
Constitutive Dyrk1A is abnormally expressed in Alzheimer disease, Down syndrome, Pick disease, and related transgenic models.
DYRK1A, dual-specificity tyrosine-regulated kinase 1A, maps to human chromosome 21 within the Down syndrome (DS) critical region. Dyrk1 phosphorylates the human microtubule-associated protein tau at Thr212 in vitro, a residue that is phosphorylated in fetal tau and hyper-phosphorylated in Alzheimer disease (AD) and tauopathies, including Pick disease (PiD). Furthermore, phosphorylation of Thr212 primes tau for phosphorylation by glycogen synthase kinase 3 (GSK-3). The present study examines Dyrk1A in the cerebral cortex of sporadic AD, adult DS with associated AD, and PiD. Increased Dyrk1A immunoreactivity has been found in the cytoplasm and nuclei of scattered neurons of the neocortex, entorhinal cortex, and hippocampus in AD, DS, and PiD. Dyrk1A is found in sarkosyl-insoluble fractions which are enriched in phosphorylated tau in AD brains, thus suggesting a possible association of Dyrk1A with neurofibrillary tangle pathology. Yet, no clear relationship has been observed between tau phosphorylation at Thr212, and GSK-3 and Dyrk1A expression in diseased brains. Transgenic mice bearing a triple tau mutation (G272V, P301L, and R406W) and expressing hyper-phosphoyrylated tau in neurons of the entorhinal cortex, hippocampus, and cerebral neocortex show increased expression of Dyrk1A in individual neurons in the same regions. However, transgenic mice over-expressing Dyrk1A do not show increased phosphorylation of tau at Thr212, thus suggesting that Dyrk1A over-expression does not trigger per se hyper-phosphorylation of tau at Thr212 in vivo. The present observations indicate modifications in the expression of constitutive Dyrk1A in the cytoplasm and nuclei of neurons in various neurodegenerative diseases associated with tau phosphorylation.
Adult↗
Abnormal group I metabotropic glutamate receptor expression and signaling in the frontal cortex in Pick disease.
Group I metabotropic glutamate receptors (mGluR1) regulate synaptic transmission through the stimulation of phospholipase Cbeta1 (PLCbeta1) and then by the activation of protein kinase C (PKC). Considering these properties, it is conceivable that major cortical functional deficits may be attributed to abnormal mGluR processing and signaling. The present work examines mGluRI expression and signaling in the frontal cortex (area 8) of 3 cases with Pick disease (PiD), a neurodegenerative disease with abnormal phospho-tau accumulation, in comparison with 3 age-matched controls by means of glutamate binding assays, enzymatic activity, gel electrophoresis and Western blotting, solubility and immunoprecipitation assays, and confocal microscopy. Reduced expression levels of PLCbeta1 and reduced PLCbeta1 activity have been found in PiD. The expression levels of the nonrelated phospholipase PLCgamma, a substrate of tyrosine kinase, are also reduced in PiD. This is accompanied by a marked decrease in the expression of cPKCalpha and increased expression of the inner band (76 kDa) of the nPKCdelta doublet at the expense of a decrease of the phosphorylated (active) form (78 kDa). In contrast, L-[3H]glutamate-specific binding to mGluRs is augmented in PiD cases, mainly because of the higher mGluR1 and mGluRs expression levels detected. No modifications in PLCbeta1 solubility have been observed in PiD and no interactions between PLCbeta1 and tau have been demonstrated in diseased and control cases. Moreover, double-labeling immunofluorescence and confocal microscopy have shown no colocalization of phospho-tau (AT8 antibody) and PLCbeta1 in phospho-tau inclusions, including Pick bodies. These results demontrate for the first time abnormal mGluR signaling in the cerebral cortex in PiD and selective vulnerability of phospholipases and PKC to PiD.
Aged↗
Upregulation of amyloid precursor protein isoforms containing Kunitz protease inhibitor in dementia with Lewy bodies.
Amyloid precursor protein (APP) is involved in the accumulation of alpha-synuclein, the main component of Lewy bodies. It is currently unknown, however, whether any of the APP isoforms is instrumental in alpha-synuclein deposition in dementia with Lewy bodies (DLB). Using real-time RT-PCR, we have studied relative mRNA expression levels of APP isoforms in frozen postmortem frontal cortices of DLB patients, Alzheimer disease (AD) patients, and control subjects. Of the three main APP isoforms, the two with a Kunitz protease inhibitory (KPI) motif (APP770 and APP751) were found to be specifically overexpressed in the frontal cortices of DLB patients when compared with controls and AD patients. These findings suggest a specific role of APP isoforms containing Kunitz protease inhibitor in DLB pathogenesis.
Aged↗
Amyloid-beta deposition in the cerebral cortex in Dementia with Lewy bodies is accompanied by a relative increase in AbetaPP mRNA isoforms containing the Kunitz protease inhibitor.
Deposition of amyloid-beta, the fibrillogenic product of the cell surface protein AbetaPP (amyloid-beta protein precursor), occurs in the cerebral cortex of patients with Dementia with Lewy bodies (DLB). Amyloid deposition, basically in the form of senile plaques, occurs not only in the common form (DLBc), which is defined by changes consistent with diffuse Lewy body disease accompanied by Alzheimer's disease (AD), but also in the pure form (DLBp), in which neurofibrillary tangles are absent. The present study analyses the expression of AbetaPP mRNA isoforms with (AbetaPP751 and AbetaPP770) and without (AbetaPP695) the Kunitz-type serine protease inhibitor (KPI) domain, in the cerebral cortex in DLBc (n=4), DLBp (n=4), Parkinson's disease (PD, n=5), AD (n=3 stages I-IIA, and n=4 stage VC of Braak and Braak), amyloid angiopathy (AA, n=2) and progressive supranuclear palsy (PSP, n=4) compared with age-matched controls (n=6). For this purpose, TaqMan RT-PCR assay was used on frozen post-mortem samples of the frontal cortex (area 8) obtained with short post-mortem delays (8.29+/-4.57 h) and strict RNA preservation (A260/280 of 1.78+/-0.15). A 3.66-fold, 6.67-fold, 4.28-fold and 5.24-fold increases, in the (AbetaPP751+AbetaPP770)/AbetaPP695 mRNA ratio were found in DLBc, DLBp, AD stage VC and AA, respectively, when compared with controls. No modifications in the ratio were found in PD, AD stage I-IIA and PSP. These findings suggest that alternative splicing of the AbetaPP mRNA may play a role in betaA4 amyloidogenesis in DLBp, DLBc, AD stage VC and Amyloid angiopathy.
Adult↗
Biochemical, ultrastructural, and reversibility studies on huntingtin filaments isolated from mouse and human brain.
Huntington's disease (HD) and eight additional inherited neurological disorders are caused by CAG triplet-repeat expansions leading to expanded polyglutamine-sequences in their respective proteins. These triplet-CAG repeat disorders have in common the formation of aberrant intraneuronal proteinaceous inclusions containing the expanded polyglutamine sequences. These aggregates have been postulated to contribute to pathogenesis caused by conformational toxicity, sequestration of other polyglutamine-containing proteins, or by interfering with certain enzymatic activities. Testing these hypotheses has been hampered by the difficulty to isolate these aggregates from brain. Here we report that polyglutamine aggregates can be isolated from the brain of the Tet/HD94 conditional mouse model of HD, by following a method based on high salt buffer homogenization, nonionic detergent extraction, and gradient fractionation. We then verified that the method can be successfully applied to postmortem HD brains. Immunoelectron microscopy, both in human and mouse samples, revealed that the stable component of the inclusions are mutant huntingtin-containing and ubiquitin-containing fibrils. Atomic-force microscopy revealed that these fibrils have a "beads on a string" morphology. Thus, they resemble the in vitro assembled filaments made of recombinant mutant-huntingtin, as well as the Abeta and alpha-synuclein amyloid protofibrils. Finally, by shutting down transgene expression in the Tet/HD94 conditional mouse model of HD, we were able to demonstrate that these filaments, although stable in vitro, are susceptible to revert in vivo, thus demonstrating that the previously reported reversal of ubiquitin-immunoreactive inclusions does not simply reflect disassembling of the inclusions into their constituent fibrils and suggesting that any associated conformational or protein-sequestration toxicity is also likely to revert.
Aged↗
alpha-Synuclein expression levels do not significantly affect proteasome function and expression in mice and stably transfected PC12 cell lines.
alpha-Synuclein (alpha-syn) is a small protein of unknown function that is found aggregated in Lewy bodies, the histopathological hallmark of sporadic Parkinson disease and other synucleinopathies. Mutations in the alpha-syn gene and a triplication of its gene locus have been identified in early onset familial Parkinson disease. alpha-Syn turnover can be mediated by the proteasome pathway. A survey of published data may lead to the suggestion that overexpression of alpha-syn wild type, and/or their variants (A53T and A30P), may produce a decrease in proteasome activity and function, contributing to alpha-syn aggregation. To investigate the relationship between synuclein expression and proteasome function we have studied proteasome peptidase activities and proteasome subunit expression (alpha, beta-constitutive, and inducible) in mice either lacking alpha-syn (knock-out mice) or transgenic for human alpha-syn A30P (under control of PrP promoter, at a time when no clear gliosis can be observed). Similar studies are presented in PC12 cells overexpressing enhanced yellow fluorescent protein fusion constructs of human wild type, A30P, and A53T alpha-syn. In these cell lines we have also analyzed the assembly of 20 S proteasome complex and the degradation rate of a well known substrate of the proteasome pathway, Ikappabalpha. Overall the data obtained led us to the conclusion that alpha-synuclein expression levels by themselves have no significant effect on proteasome peptidase activity, subunit expression, and proteasome complex assembly and function. These results strengthen the suggestion that other mechanisms resulting in synuclein aggregation (not simply expression levels) may be the key to understand the possible effect of aggregated synuclein on proteasome function.
Animals↗
Desmin-related myopathy: clinical, electrophysiological, radiological, neuropathological and genetic studies.
Ten Spanish patients from six unrelated families diagnosed with desmin-related myopathy (DRM) were studied. The pattern of DRM inheritance was autosomal dominant in three families, autosomal recessive in one, and there was no family history in two cases. The disease onset was in early adulthood. Cardiac myopathy was the initial presentation in two patients, respiratory insufficiency in one, and lower limb weakness in all others. Cardiac involvement was observed in four patients. Lens opacities were found in four. CK level was normal or slightly elevated, and electrophysiological examination was consistent with myopathy. Muscle biopsies identified intracytoplasmic desmin-immunoreactive inclusions. In addition to desmin, synemin, actin, gelsolin, ubiquitin, alphaB-crystallin and amyloid betaA4 were also present in the deposits. Ultrastructural examination revealed areas of myofibrillary disruption, abnormal electron-dense structures and accumulations of granulofilamentous material. A missense R406W mutation and a novel single amino acid deletion in the desmin gene were identified in two patients; the other patients did not show mutations in desmin, synemin, syncoilin or alphaB-crystallin genes. Analysis of 10 Spanish DRM cases illustrates a wide clinical, myopathological and genetic spectrum of DRM, reinforcing the need for further exploration of genetic causes for this group of disorders.
Adolescent↗
Overexpression of semicarbazide-sensitive amine oxidase in human myopathies.
Oxidative stress has been implicated in the pathogenesis of several muscle diseases. Semicarbazide-sensitive amine oxidase (SSAO) metabolizes oxidative deamination of primary aromatic and aliphatic amines. In the oxidative reactions, amine substrates are converted into the aldehyde, followed by the production of ammonia and H(2)O(2). Although normal levels in muscle are very low, SSAO is expressed in almost all mammalian tissues. In this study, we examined the possible implication of SSAO as an additional source of oxidative stress in the pathogenesis of muscle disorders. The expression of SSAO was examined immunohistochemically in muscle biopsy specimens from patients with inclusion-body myositis (IBM; n = 5), desmin-related myopathy (DRM; n = 3), dermatomyositis (n = 3), granulomatous (sarcoid) myopathy (n = 2), muscle denervation-reinnervation (n = 3), and rhabdomyolysis (n = 2), as well as from control subjects (n = 3). Strong SSAO immunoreactivity was present in vacuolated and nonvacuolated fibers in IBM, in abnormal fibers in DRM, and in degenerating and regenerating fibers in dermatomyositis and rhabdomyolysis. In addition, SSAO overexpression was observed in muscle fibers adjacent to granulomas in sarcoid myopathy. These results suggest that SSAO is a source of oxidative stress in diseased human skeletal muscle and that it contributes to oxidative stress-induced damage in various inflammatory and other myopathies. Alternatively, the expression of SSAO in muscle fibers may be a consequence of muscle fiber injury.
Aged↗
A series of West European patients with severe cardiac and skeletal myopathy associated with a de novo R406W mutation in desmin.
Desminopathy is a familial or sporadic cardiac and skeletal muscular dystrophy associated with mutations in desmin. We have previously characterized a de novo desmin R406W mutation in a patient of European origin with early onset muscle weakness in the lower extremities and atrioventricular conduction block requiring a permanent pacemaker. The disease relentlessly progressed resulting in severe incapacity within 5 years after onset. We have now identified three other patients with early onset rapidly progressive cardiac and skeletal myopathy caused by this same desmin R406W mutation. The mutation was present in each studied patient, but not in their parents or other unaffected family members, indicating that the mutation in all four cases was generated de novo. The patients' mutation-carrying chromosomes showed no similarity, suggesting that the R406W mutation has occurred independently. These observations strongly confirm that the de novo R406W desmin mutation is the genetic basis for early-onset cardiac and skeletal myopathy in patients with sporadic disease and indicate that desmin position 406 is a hot spot for spontaneous mutations. The high pathogenic potential of this mutation can be explained by its location in the highly conserved YRKLLEGEE motif at the C-terminal end of the 2B helix that has a critical role in the process of desmin filament assembly.
Adolescent↗
A novel mutation in the caveolin-3 gene causing familial isolated hyperCKaemia.
Three members of a family were known to have persistent elevated serum CK levels without muscle weakness. A muscle biopsy showed a partial reduction of caveolin-3 at the sarcolemma of muscle fibres, which was confirmed by Western blot analysis. Mutational analysis identified a novel heterozygous mutation: G-->A transition at nucleotide position 169 in exon 2 in the CAV-3 gene, generating a Val-->Met change at codon 57 of the aminoacid chain. This is the second mutation in the CAV-3 gene associated with familial isolated hyperCKaemia.
Adolescent↗
DNA chip technology in brain banks: confronting a degrading world.
DNA microarray technology is based on the principle of hybridization between 2 complementary strands of nucleic acids, one being fixed into a solid membrane, the other being the sample to analyze. This has resulted in a very powerful method to examine differential gene expression between samples, and has been widely used in the study of tumors. The application of DNA microarray technology to the study of the nervous system has to consider several properties of the nervous tissue: composition of various neuronal types, as well as astrocytes, oligodendrocytes, and microglia; regional and area differences; developmental and age-dependent variations; and functional and pathological status. Moreover, human samples are usually obtained postmortem following variable agonal periods and postmortem delays between death and tissue preservation, which are accompanied by variable RNA degradation. Yet human postmortem nervous tissue stored in brain banks offers a unique opportunity to facilitate material for the study of diseases of the nervous system and to gain direct understanding on the mechanisms of disease. This review analyzes the application of DNA microarray technology to current practice using brain-banked tissues in order to recognize and minimize sub-optimal processing of brain samples and to correct pitfalls due to inadequate procedures. Also discussed are RNA preservation and RNA degradation effects on expression pattern assessments, analysis of individual versus pooled samples, array normalization, types of DNA chip platforms, whole genomic analysis versus specialized chips, and microgenomics. Minimizing RNA degradation and improving detection of resistant RNA in postmortem brain has been considered in detail in order to improve the efficiency and reliability of DNA microarray technology employed in the study of human postmortem nervous tissue.
Animals↗
Proteasomal expression, induction of immunoproteasome subunits, and local MHC class I presentation in myofibrillar myopathy and inclusion body myositis.
Inclusion body myositis (IBM) and myofibrillar myopathy (MM) are diseases characterized by the abnormal accumulation of proteins in muscle fibers, including desmin, alphaB-crystallin, gelsolin, actin, kinases, and phospho-tau, along with ubiquitin in muscle fibers, suggesting abnormal protein degradation as a possible cause of the surplus myopathy. Since the ubiquitin-proteasome system plays a crucial role in non-lysosomal protein degradation, the present study has examined by immunohistochemistry the expression of components of the catalytic core of 20S proteasomes and its regulators: 19S and PA28alpha/beta, and the expression of immunoproteasome subunits LMP2, LMP7, and MECL1 in 8 patients with MM and 10 patients with IBM. The patients with MM were from 6 unrelated families, 2 sporadic cases, I with autosomal recessive and 5 with autosomal dominant inheritance. One sporadic patient had a de novo R406W mutation in the desmin gene, and 1 patient with autosomal dominant MM had a single amino acid deletion at position 366 in the desmin gene. Increased immunoreactivity to 20S, 19S, and PA28alpha/beta colocalizing abnormal protein deposits, as revealed in consecutive serial sections, was seen in all cases with MM and IBM. In all cases, the subunits of the immunoproteasome LMP2, LMP7, and MECL1 colocalized with proteasomal immunoreactivity and abnormal protein accumulation. Immunohistochemistry revealed focal MHC class I immunoreactivity in the cytoplasmic membrane of muscle fibers in IBM and in association with protein aggregates in IBM, and to a lesser degree, in MM. The present findings provide a link between abnormal protein accumulation and altered proteasomal expression in IBM and MM.
Adenosine Triphosphatases↗
Neuronal induction of the immunoproteasome in Huntington's disease.
Huntington's disease (HD) inclusions are stained with anti-ubiquitin and anti-proteasome antibodies. This, together with proteasome activity studies on transfected cells, suggest that an impairment of the ubiquitin-proteasome system (UPS) may be key in HD pathogenesis. To test whether proteasome activity is impaired in vivo, we performed enzymatic assays for the three peptidase activities of the proteasome in brain extracts from the HD94 conditional mouse model of HD. We found no inhibition of any of the activities, suggesting that if UPS impairment happens in vivo, it is not at the level of the proteasome catalytic core. Intriguingly, the chymotrypsin- and trypsin-like activities increased selectively in the affected and aggregate-containing regions: cortex and striatum. Western blot analysis revealed no difference in total proteasome content whereas an increase in the interferon-inducible subunits of the immunoproteasome, LMP2 and LMP7, was observed. These subunits confer to the proteasome catalytic properties that are optimal for MHC-I peptide presentation. Immunohistochemistry in control mouse brain revealed LMP2 and LMP7 mainly in neurons. Accordingly, their increase in HD94 mice predominantly took place in neurons, and 5% of the ubiquitin-positive cortical aggregates were also LMP2-positive. Ultrastructural analysis of neurons with high level of immunoproteasome subunits revealed signs of neurodegeneration like nuclear indentation or fragmentation and dark cell appearance. The neuronal induction of LMP2 and LMP7 and the associated signs of neurodegeneration were also found in HD postmortem brains. Our results indicate that LMP2 and LMP7 participate in normal neuronal physiology and suggest a role in HD neurodegeneration.
Aged↗
Small deletions disturb desmin architecture leading to breakdown of muscle cells and development of skeletal or cardioskeletal myopathy.
Desmin ( DES) mutations have been recognized as a cause of desmin-related myopathy (OMIM 601419), or desminopathy, a disease characterized by progressive limb muscle weakness and accumulation of desmin-reactive granular aggregates in the myofibers. We have studied three families with skeletal or cardioskeletal myopathy caused by small in-frame deletions in the desmin gene. The newly identified in-frame deletions E359_S361del and N366del alter the heptad periodicity within a critical 2B coiled-coil segment. Structural analysis reveals that the E359_S361 deletion introduces a second stutter immediately downstream of the naturally occurring stutter, thus doubling the extent of the local coiled-coil unwinding. The N366del mutation converts the wild-type stutter into a different type of discontinuity, a stammer. A stammer, as opposed to a stutter, is expected to cause an extra overwinding of the coiled-coil. These mutations alter the coiled-coil geometry in specific ways leading to fatal damage to desmin filament assembly. Expression studies in two cell lines confirm the inability of desmin molecules with this changed architecture to polymerize into a functional filamentous network. This study provides insights into molecular pathogenetic mechanisms of desmin mutation-associated skeletal and cardioskeletal myopathy.
Adult↗
Neuroprotective effect of citicoline in 6-hydroxydopamine-lesioned rats and in 6-hydroxydopamine-treated SH-SY5Y human neuroblastoma cells.
Citicoline (CDP-choline or cytidine 5'-diphosphocholine) has been used as a therapeutic agent in combination with levodopa in the treatment of Parkinson's disease (PD). The present study examines the effects of citicoline by using validated in vivo and in vitro models. Citicoline reduces the cytotoxic effect of 6-hydroxydopamine (6-OHDA)-treated human dopaminergic SH-SY5Y neuroblastoma cells as measured cellular redox activity with 3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyltetrazolium bromide (MTT) and increases the levels of reduced glutathione (GSH), a major antioxidant agent. Moreover, citicoline (500 mg/kg i.p.) administered for 7 days ameliorates functional behaviour by significantly reducing the number of apomorphine-induced contralateral rotations in 6-OHDA rats. Finally, citicoline significantly attenuates substantia nigra (SN) dopaminergic cell dropout and tyrosine hydroxylase immunoreactivity in the ipsilateral striatum in rats injected intrastriatally with 6-hydroxydopamine (6-OHDA).
Animals↗
Expression of the intermediate filament protein synemin in myofibrillar myopathies and other muscle diseases.
Synemin is a member of the intermediate protein superfamily. Previous studies in avian and rodent skeletal and cardiac muscles have demonstrated that synemin localises at the Z-band, where it associates with desmin and alpha-actinin. In the present study, the distribution of synemin was examined using immunohistochemistry in muscle biopsy specimens from patients suffering from myofibrillar myopathy (MM, n=6), dermatomyositis (DM, n=3), inclusion body myositis (IBM, n=5), oculopharyngeal muscular dystrophy (OPD, n=3) and denervation atrophy (DA, n=3), to investigate the possible participation of this protein in the pathogenesis of various muscular diseases. Of patients affected by MM, two showed the presence of mutations in the desmin gene; none had mutations in the alphaB-crystallin gene; and no mutations were identified in synemin or syncoilin genes of three patients. Synemin immunohistochemistry disclosed a faint staining corresponding to the Z-bands in the cytoplasm of control muscle fibres; in contrast, focal aggregates of synemin were seen in patients with MM. Increased synemin immunoreactivity was identified diffusely or in the subsarcolemmal space of scattered fibres in patients with DM, and in vacuolated fibres of patients with IBM and OPD. Strong synemin immunoreactivity was observed in target formations and atrophic fibres of patients with denervating disorders, as well as in atrophic fibres, regardless of their origin, in all patients studied. Synemin co-localised with desmin, as seen on consecutive serial sections immunostained with anti-synemin or anti-desmin antibodies. These observations demonstrate abnormal accumulations containing both synemin and desmin in muscle fibres in patients with MM, IBM, DM, OPD and DA. Considering the important role of synemin as one of intermediate filaments of skeletal and cardiac muscle, its destruction and accumulation in the intracellular debris suggest that synemin may participate in the pathogenesis of these disorders.
Adult↗
Dyrk1A expression pattern supports specific roles of this kinase in the adult central nervous system.
Dyrk1A and its Drosophila orthologue, the protein minibrain (mnb), belong to a family of serine/threonine kinases involved in the development of the central nervous system (CNS). However, additional roles for Dyrk1A have to be proposed, as its expression is still prominent in the adult brain. To gain insight into Dyrk1A physiological roles we have studied the distribution of this kinase in the CNS of mice in adulthood. A homogeneous diffuse immunostaining of variable intensity was detected throughout the neuropile, with the white matter displaying faint Dyrk1A immunoreactivity. Dyrk1A immunostaining was strong in the olfactory bulb, the cerebellar cortex and functionally related structures, the spinal cord and most of the motor nuclei of the midbrain and brain stem. These data agree with a possible implication of this kinase in the physiology of olfaction and motor functions. Cellular and subcellular localisation of Dyrk1A was also studied in primary cell culture of cerebellum, one of the structures showing significant Dyrk1A immunostaining in the adult. The distribution of Dyrk1A in primary cell culture showed the presence of this protein in the nucleus and the cytoplasm of both neurons and astrocytes. Moreover, studies on the subcellular distribution of Dyrk1A in whole brain homogenates of adult mice showed the presence of this protein both in nuclear and cytoplasm-enriched fractions, thus supporting selective functions of this kinase in these two subcellular compartments. The present results showing the distribution of Dyrk1A in widespread areas of the adult CNS and in different subcellular compartments, together with previous reports demonstrating its implication in developmental events concur with the idea of several spatio-temporal functional profiles.
Animals↗