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Clifford W Shults

Publications and source records attributed to Clifford W Shults.

At least 19 recordsLinked to original sources
PubMed2007

G2019S mutation in the leucine-rich repeat kinase 2 gene is not associated with multiple system atrophy.

Multiple system atrophy (MSA) is characterized clinically by Parkinsonism, cerebellar dysfunction, and autonomic impairment. Multiple mutations in the LRRK2 gene are associated with parkinsonian disorders, and the most common one, the G2019S mutation, has been found in approximately 1% of sporadic cases of Parkinsonism. In a well-characterized cohort of 136 subjects with probable MSA and 110 neurologically evaluated control subjects, none carried the G2019S mutation. We conclude that the G2019S mutation in the LRRK2 gene is unlikely to be associated with MSA.

Cerebellum↗
PubMed2007

R1514Q substitution in Lrrk2 is not a pathogenic Parkinson's disease mutation.

Mutations in LRRK2 were first reported as causing Parkinson's disease (PD) in late 2004. Since then, approximately a dozen LRRK2 substitutions have been identified that are believed to be pathogenic mutations. The substitution of adenine for guanine at nucleotide 4541 (4541G>A) in LRRK2 was recently reported. This substitution resulted in the replacement of an arginine at position 1514 with a glutamine (R1514Q). Although this substitution was not found in a large cohort of controls, its pathogenicity could not be verified. We have now genotyped the R1514Q substitution in a sample of 954 PD patients from 429 multiplex PD families. This substitution was identified in 1.8% of the PD patients; however, the majority of the PD sibships segregating this substitution were discordant for this putative mutation. In addition, the R1514Q substitution was detected in 1.4% of neurologically evaluated, control individuals. These data suggest that the R1514Q variant is not a pathogenic LRRK2 mutation. We believe it is imperative that the causative nature of any newly identified genetic variant be determined before it is included in any panel for diagnostic testing.

Adenine Nucleotide Translocator 1↗
PubMed2006

Mutations in DJ-1 are rare in familial Parkinson disease.

Mutations in DJ-1 (PARK7) are one cause of early-onset autosomal-recessive parkinsonism. We screened for DJ-1 mutations in 93 affected individuals from the 64 multiplex Parkinson disease (PD) families in our sample that had the highest family-specific multipoint LOD scores at the DJ-1 locus. In addition to sequencing all coding exons for alterations, we used multiplex ligation-dependent probe amplification (MLPA) to examine the genomic copy number of DJ-1 exons. A known polymorphism (R98Q) was found in five PD subjects, once as a homozygote and in the other four cases as heterozygotes. No additional missense mutations and no exon deletions or duplications were detected. Our results, in combination with those of previous studies, suggest that alterations in DJ-1 are not a common cause of familial PD.

Aged↗
PubMed2006

alpha-synuclein from platelets is not phosphorylated at serine 129 in Parkinson's disease and multiple system atrophy.

Parkinson's disease (PD) and multiple system atrophy (MSA) are characterized pathologically by inclusions in the brain containing alpha-synuclein, which is phosphorylated at serine 129. alpha-Synuclein is present not only in the brain but also in platelets; platelets have previously been used to study mitochondrial function in PD. We undertook to determine whether alpha-synuclein extracted from platelets of patients with PD and MSA is phosphorylated at serine 129 and could be used as a peripheral marker of these disorders. Immunoblots indicated that platelet alpha-synuclein is not phosphorylated at serine 129 in PD and MSA.

Adult↗
PubMed2006

Lewy bodies.

Lewy bodies (LB) in the substantia nigra are a cardinal pathological feature of Parkinson's disease, but they occur in a number of neurodegenerative diseases and can be widespread in the nervous system. The characteristics, locations, and composition of LB are reviewed, with particular attention to alpha-synuclein (alpha-SYN), which appears to be the major component of LB. The propensity for alpha-SYN, a presynaptic protein widely expressed in the brain, to aggregate is because of an amyloidogenic central region. The factors that favor the aggregation of alpha-SYN and mechanisms of toxicity are examined, and a mechanism through which aggregates of alpha-SYN could induce mitochondrial dysfunction and/or release of proapoptotic molecules is proposed.

Animals↗
PubMed2006

Presence of an APOE4 allele results in significantly earlier onset of Parkinson's disease and a higher risk with dementia.

The epsilon4 allele of the apolipoprotein E gene (APOE4) has been consistently associated with a greater risk of Alzheimer's disease (AD) as well as an earlier onset of AD. It is possible that APOE4 may also play a role in the etiology of other neurodegenerative disorders, such as Parkinson's disease (PD). APOE genotype, age of onset, disease duration, smoking history, and dementia status were collected for families with PD, yielding 324 Caucasian families with complete information. Logistic regression employing one individual per family and including age of onset and disease duration as covariates demonstrated a significantly increased risk of dementia for those individuals having inherited at least one epsilon4 allele (OR=3.37; P=0.002). Survival analyses also demonstrated a significantly earlier age of onset for those subjects with at least one epsilon4 allele (59.7 years) as compared with those homozygous for the more common epsilon3 allele (62.4 years; P=0.009). Thus, consistent with previous studies, we find evidence that the presence of an epsilon4 allele results in significantly earlier onset of PD and a greater likelihood of dementia. It appears the similarities between PD and AD may be due to an overlap in the diseases' genetic etiology.

Adolescent↗
PubMed2006

Mutations in LRRK2 other than G2019S are rare in a north American-based sample of familial Parkinson's disease.

A total of 956 individuals with Parkinson's disease (PD) from 430 multiplex PD pedigrees were screened for 12 previously reported, pathogenic LRRK2 mutations: R793M, L1114L, I1371V, R1441C, R1441G, R1441H, Y1699C, M1869T, I2012T, I2020T, G2385R, and IVS31 +3G > A. Previous screening identified the LRRK2 G2019S mutation in 5% of our families. Only 1 of the 12 newly screened mutations, R1441C, was detected in a single family in our patient cohort. These results indicate that, although the G2019S mutation remains the most common mutation identified in familial PD patients, other mutations in LRRK2 are infrequent.

Adolescent↗
PubMed2005

Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy.

Multiple system atrophy (MSA) is a progressive, neurodegenerative disease characterized by parkinsonism, ataxia, autonomic dysfunction, and accumulation of alpha-synuclein (alpha-syn) in oligodendrocytes. To better understand the mechanisms of neurodegeneration and the role of alpha-syn accumulation in oligodendrocytes in the pathogenesis of MSA, we generated transgenic mouse lines expressing human (h) alpha-syn under the control of the murine myelin basic protein promoter. Transgenic mice expressing high levels of halpha-syn displayed severe neurological alterations and died prematurely at 6 months of age. Furthermore, mice developed progressive accumulation of halpha-syn-immunoreactive inclusions in oligodendrocytes along the axonal tracts in the brainstem, basal ganglia, cerebellum, corpus callosum, and neocortex. The inclusions also reacted with antibodies against phospho-serine (129) halpha-syn and ubiquitin, and halpha-syn was found in the detergent-insoluble fraction. In high-expresser lines, the white matter tracts displayed intense astrogliosis, myelin pallor, and decreased neurofilament immunostaining. Accumulation of halpha-syn in oligodendrocytes also leads to prominent neurodegenerative changes in the neocortex with decreased dendritic density and to loss of dopaminergic fibers in the basal ganglia. The oligodendrocytic inclusions were composed of fibrils and accompanied by mitochondrial alterations and disruption of the myelin lamina in the axons. Together, these studies support the contention that accumulation of alpha-syn in oligodendrocytes promotes neurodegeneration and recapitulates several of the key functional and neuropathological features of MSA.

Animals↗
PubMed2005

Therapeutic role of coenzyme Q(10) in Parkinson's disease.

Mitochondrial dysfunction has been well established to occur in Parkinson's disease (PD) and appears to play a role in the pathogenesis of the disorder. A key component of the mitochondrial electron transport chain (ETC) is coenzyme Q(10), which not only serves as the electron acceptor for complexes I and II of the ETC but is also an antioxidant. In addition to being crucial to the bioenergetics of the cell, mitochondria play a central role in apoptotic cell death through a number of mechanisms, and coenzyme Q(10) can affect certain of these processes. Levels of coenzyme Q(10) have been reported to be decreased in blood and platelet mitochondria from PD patients. A number of preclinical studies in in vitro and in vivo models of PD have demonstrated that coenzyme Q(10) can protect the nigrostriatal dopaminergic system. A phase II trial of coenzyme Q(10) in patients with early, untreated PD demonstrated a positive trend for coenzyme Q(10) to slow progressive disability that occurs in PD.

Animals↗
PubMed2005

Alpha-synuclein overexpression in oligodendrocytic cells results in impaired adhesion to fibronectin and cell death.

The cardinal pathological features of multiple system atrophy (MSA) are the presence of glial cytoplasmic inclusions (GCIs) in oligodendrocytes and loss of oligodendrocytes. To understand the mechanisms underlying MSA, we examined the effects of overexpression of human alpha-synuclein (halpha-syn) in CG-4 oligodendrocytic progenitor cells. CG-4 cells overexpressing halpha-syn (halpha-syn CG-4) demonstrated severely impaired adhesion and increased cell death when plated on fibronectin compared to laminin. The expression of the alphav integrin subunit in whole cell lysates was also significantly downregulated in halpha-syn CG-4. These results demonstrate a cytotoxic consequence of halpha-syn overexpression in CG-4. This cytotoxicity appears to be the result of alterations in cell-extracellular matrix interactions, where impaired adhesion to fibronectin is associated with downregulation of the alphav integrin subunit and increased cell death. It may, therefore, be one of the mechanisms underlying the loss of oligodendrocytes in MSA.

Animals↗
PubMed2004

Mitochondrial dysfunction and possible treatments in Parkinson's disease--a review.

Mitochondria are central not only to the bioenergetics of the cell but also to the process of apoptotic cell death. Substantial data indicate mitochondrial dysfunction, particularly of complex I of the electron transport chain, in some patients with Parkinson's disease (PD), and it appears likely that mitochondria contribute to the pathogenic processes that occurs in this disorder. Treatments targeted at mitochondrial function hold promise to slow the progression of PD.

Journal Article↗
PubMed2004

Evaluation of the role of Nurr1 in a large sample of familial Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder in humans with wide variability in the age of disease onset. Although the disease has been thought previously to occur sporadically in most patients, there is increasing evidence of a genetic contribution to the disorder. Recently, a polymorphic variant within intron 6 of the Nurr1 gene was reported to be associated with sporadic and familial PD. In an effort to identify susceptibility genes for PD, we have collected 783 PD patients from 372 families and 397 healthy controls from 217 families. PD patients and healthy controls were genotyped for the intron 6 insertion polymorphism by BseRI restriction endonuclease digestion. No significant difference in either homozygosity or heterozygosity for the 7048G7049 (IVS6 1361 +16insG) polymorphism was detected in the PD patient cohort as compared with the panel of healthy controls. Moreover, direct sequencing of exon 1 of the Nurr1 gene in PD patients failed to detect either of the two recently reported Nurr1 mutations identified in a small subset of a PD patient cohort. Taken together, these data suggest that genetic alteration at the Nurr1 locus is not a significant risk factor for the development of Parkinson's disease in our large sample of familial PD patients.

Adolescent↗
PubMed2004

Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS).

We aimed to develop and validate a novel rating scale for multiple system atrophy (Unified Multiple System Atrophy Rating Scale-UMSARS). The scale comprises the following components: Part I, historical, 12 items; Part II, motor examination, 14 items; Part III, autonomic examination; and Part IV, global disability scale. For validation purposes, 40 MSA patients were assessed in four centers by 4 raters per center (2 senior and 2 junior raters). The raters applied the UMSARS, as well as a range of other scales, including the Unified Parkinson's Disease Rating Scale (UPDRS) and the International Cooperative Ataxia Rating Scale (ICARS). Internal consistency was high for both UMSARS-I (Crohnbach's alpha = 0.84) and UMSARS-II (Crohnbach's alpha = 0.90) sections. The interrater reliability of most of the UMSARS-I and -II items as well as of total UMSARS-I and -II subscores was substantial (k(w) = 0.6-0.8) to excellent (k(w) > 0.8). UMSARS-II correlated well with UPDRS-III and ICARS (rs > 0.8). Depending on the degree of the patient's disability, completion of the entire UMSARS took 30 to 45 minutes. Based on our findings, the UMSARS appears to be a multidimensional, reliable, and valid scale for semiquantitative clinical assessments of MSA patients.

Activities of Daily Living↗
PubMed2004

Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson's disease.

The safety and tolerability of high dosages of coenzyme Q10 were studied in 17 patients with Parkinson's disease (PD) in an open label study. The subjects received an escalating dosage of coenzyme Q10--1200, 1800, 2400, and 3000 mg/day with a stable dosage of vitamin E (alpha-tocopherol) 1200 IU/day. The plasma level of coenzyme Q10 was measured at each dosage. Thirteen of the subjects achieved the maximal dosage, and adverse events were typically considered to be unrelated to coenzyme Q10. The plasma level reached a plateau at the 2400 mg/day dosage and did not increase further at the 3000 mg/day dosage. Our data suggest that in future studies of coenzyme Q10 in PD, a dosage of 2400 mg/day (with vitamin E/alpha-tocopherol 1200 IU/day) is an appropriate highest dosage to be studied.

Calcium↗
PubMed2004

Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP.

Recent studies have implicated alpha-synuclein (alpha-S) in the pathogenesis of Parkinson's disease (PD). The mechanisms underlying PD are not completely understood; however, mitochondrial complex I inhibition and oxidative injury may be involved. Because the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent complex I inhibitor that can cause oxidative injury and mimic many aspects of PD in treated animals, we sought to determine whether the overexpression of alpha-S in transgenic (tg) mice (alpha-S-tg) would enhance the substantia nigra (SN) pathology resulting from treatment with MPTP. For this purpose, alpha-S-tg mice were produced expressing high levels of wild-type (wt) human alpha-S under the control of the neuron-specific Thy-1 promoter. Alpha-S-tg mice and non-tg controls were treated with MPTP (15 mg/kg ip, twice a week for 2 weeks) or saline (Sal) and then examined 2 weeks after completion of treatment by transmission electron microscopy (EM). We found that alpha-S-tg mice treated with MPTP had extensive mitochondrial alterations, increases in mitochondrial size, filamentous neuritic aggregations, axonal degeneration, and formation of electron dense perinuclear cytoplasmic inclusions in the SN that did not occur in the hippocampus or neocortex, nor in MPTP-treated non-tg mice or Sal-treated alpha-S-tg mice. These findings support the potential involvement of alpha-S expression in the vulnerability of SN neurons to toxicity from mitochondrial complex I inhibitors and the subsequent development of neurodegenerative pathology.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗