alpha-synuclein and Spinocerebellar-Ataxias

Juvenile parkinsonism is arbitrarily defined as parkinsonian symptoms and signs presenting prior to 21 years of age. Levodopa-responsive juvenile parkinsonism that is consistent with diagnostic criteria for Parkinson's disease is most often caused by mutations in the PARK-Parkin, PARK-PINK1, or PARK-DJ1 genes. However, many other genetic and acquired parkinsonian disorders presenting in childhood or young adulthood are being reported, often with atypical features, such as presence of other movement disorders, cognitive decline, and psychiatric symptoms. The genetic landscape of juvenile parkinsonism is rapidly changing with the discovery of new genes. Although the mainstay of treatment remains levodopa, other symptomatic therapies such as botulinum toxin for focal dystonia, supportive medical therapies, and deep brain stimulation in select cases, may also be used to provide the most optimal long-term outcomes. Since the topic has not been reviewed recently, we aim to provide an update on genetics, differential diagnosis, evaluation, and treatment of juvenile parkinsonism.

Topics: Adolescent; alpha-Synuclein; Antiparkinson Agents; Child; Child, Preschool; Deep Brain Stimulation; Diagnosis, Differential; DiGeorge Syndrome; Dystonic Disorders; Genetic Diseases, X-Linked; Hepatolenticular Degeneration; Humans; Huntington Disease; Levodopa; Parkinsonian Disorders; Protein Deglycase DJ-1; Protein Kinases; Spinocerebellar Ataxias; Ubiquitin-Protein Ligases; Young Adult

Linkage of the Huntington's disease gene to chromosome 4 in 1983 marked the birth of modern genetics in movement disorders. The discovery that an expanded trinucleotide DNA repeat was central to the mechanism of this disease has been repeated over and over in a growing list of inherited ataxias. In 1997, a different mutation and genetic mechanism was discovered in a severe type of generalized primary torsion dystonia - Oppenheim's dystonia. Before this, only the genetic cause for rare metabolic dystonias was known, notably dopa-responsive (Segawa's) dystonia. In the same year, from the identification of mutation in the alpha-synuclein gene in rare pedigrees with autosomal dominant parkinsonism, arose the concept that Parkinson's disease may be part of a broader group of 'synucleinopathies', in which there is a fundamental defect in protein processing. In the following year, mutations in autosomal recessive juvenile onset parkinsonism were found in a gene called 'parkin'. Parkin mutations are a more common cause of parkinsonism than the rare alpha-synuclein mutations, particularly in young-onset disease. However, a most important understanding, occurring in the last year, has been the relationship between the parkin gene product, alpha-synuclein and abnormal protein degradation in the cell. A unified theory of neuronal death in Parkinson's disease is emerging, pointing to potential new therapies in the future.

Topics: alpha-Synuclein; Carrier Proteins; Chromosome Mapping; Chromosomes, Human; Dystonic Disorders; Friedreich Ataxia; Genes, Dominant; Genes, Recessive; Humans; Huntingtin Protein; Huntington Disease; Ligases; Minisatellite Repeats; Molecular Chaperones; Movement Disorders; Nerve Tissue Proteins; Nuclear Proteins; Parkinson Disease; Spinocerebellar Ataxias; Synucleins; Ubiquitin-Protein Ligases

Assessment of a series of 279 cases with Lewy body disease revealed 14 families having a family history consistent with autosomal dominant inheritance, eight of these with dominant Parkinsonism and six with dominant dementia. Analysis of the age at onset and genetic features in these families revealed significant anticipation only in a subset of parkinsonian families, with no pathological alleles for spinocerebellar ataxias or the common alpha-synuclein or LRRK2 point mutations.

Topics: Age of Onset; Aged; alpha-Synuclein; DNA Mutational Analysis; Female; Genetic Testing; Genotype; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lewy Body Disease; Male; Middle Aged; Parkinson Disease; Penetrance; Predictive Value of Tests; Prospective Studies; Protein Serine-Threonine Kinases; Spinocerebellar Ataxias; Trinucleotide Repeats

The polyglutamine (polyQ) diseases, such as Huntington's disease and the spinocerebellar ataxias, are characterized by the accumulation of elongated polyQ sequences (epolyQ) and mostly occur during midlife. Considering that polyQ disorders have not been selected out in evolution, there might be important physiological functions of epolyQ during development and/or reproduction. In a similar context, the physiological functions of neurodegeneration-associated amyloidogenic proteins (APs), such as β-amyloid in Alzheimer's disease and α-synuclein in Parkinson's disease, remain elusive. In this regard, we recently proposed that evolvability for coping with diverse stressors in the brain, which is beneficial for offspring, might be relevant to the physiological functions of APs. Given analogous properties of APs and epolyQ in terms of neurotoxic amyloid-fibril formation, the objective of this paper is to determine whether evolvability could also be applied to the physiological functions of epolyQ. Indeed, APs and epolyQ are similar in many ways, including functional redundancy of non-amyloidogenic homologues, hormesis conferred by the heterogeneity of the stress-induced protein aggregates, the transgenerational prion-like transmission of the protein aggregates via germ cells, and the antagonistic pleiotropy relationship between evolvability and neurodegenerative disease. Given that epolyQ is widely expressed from microorganisms to human brain, whereas APs are only identified in vertebrates, evolvability of epolyQ is considered to be much more primitive compared to those of APs during evolution. Collectively, epolyQ may be not only be important in the pathophysiology of polyQ diseases, but also in the evolution of amyloid-related evolvability.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Bulbo-Spinal Atrophy, X-Linked; Evolution, Molecular; Genetic Pleiotropy; Humans; Huntington Disease; Machado-Joseph Disease; Myoclonic Epilepsies, Progressive; Parkinson Disease; Peptides; Spinocerebellar Ataxias; Trinucleotide Repeat Expansion

Neurodegenerative diseases, including the spinocerebellar ataxias (SCA), would benefit from the identification of reliable biomarkers that could serve as disease subtype-specific and stage-specific indicators for the development and monitoring of treatments. We analyzed the cerebrospinal fluid (CSF) level of tau, α-synuclein, DJ-1, and glial fibrillary acidic protein (GFAP), proteins previously associated with neurodegenerative processes, in patients with the autosomal dominant SCA1, SCA2, and SCA6, and the sporadic disease multiple system atrophy, cerebellar type (MSA-C), compared with age-matched controls. We estimated disease severity using the Scale for the Assessment and Rating of Ataxia (SARA). Most proteins measured trended higher in disease versus control group yet did not reach statistical significance. We found the levels of tau in both SCA2 and MSA-C patients were significantly higher than control. We found that α-synuclein levels were lower with higher SARA scores in SCA1 and tau levels were higher with greater SARA in MSA-C, although this final correlation did not reach statistical significance after post hoc correction. Additional studies with larger sample sizes are needed to improve the power of these studies and validate the use of CSF biomarkers in SCA and MSA-C.

Topics: Adult; Aged; alpha-Synuclein; Biomarkers; Female; Glial Fibrillary Acidic Protein; HSP40 Heat-Shock Proteins; Humans; Male; Middle Aged; Spinocerebellar Ataxias; tau Proteins

Mutations in the SPG7 gene are the most frequent cause of autosomal recessive hereditary spastic paraplegias and spastic ataxias. Ala510Val is the most common SPG7 mutation, with a frequency of up to 1% in the general population. Here we report the clinical, genetic, and neuropathological findings in a homozygous Ala510Val SPG7 case with spastic ataxia. Neuron loss with associated gliosis was found in the inferior olivary nucleus, the dentate nucleus of the cerebellum, the substantia nigra and the basal nucleus of Meynert. Neurofilament and/or paraplegin accumulation was observed in swollen neurites in the cerebellar and cerebral cortex. This case also showed subcortical τ-pathology in an unique distribution pattern largely restricted to the brainstem. α-synuclein containing Lewy bodies (LBs) were observed in the brainstem and the cortex, compatible with a limbic pattern of Braak LB-Disease stage 4. Taken together, this case shows that the spectrum of pathologies in SPG7 can include neuron loss of the dentate nucleus and the inferior olivary nucleus as well as neuritic pathology. The progressive supranuclear palsy-like brainstem predominant pattern of τ pathology and α-synuclein containing Lewy bodies in our SPG7 cases may be either coincidental or related to SPG7 in addition to neuron loss and neuritic pathology.

Topics: Aged; alpha-Synuclein; ATPases Associated with Diverse Cellular Activities; Basal Nucleus of Meynert; Cerebellar Nuclei; Gene Frequency; Gliosis; Humans; Intellectual Disability; Lewy Bodies; Male; Metalloendopeptidases; Muscle Spasticity; Neurites; Neurofibrillary Tangles; Neurons; Olivary Nucleus; Optic Atrophy; Spastic Paraplegia, Hereditary; Spinocerebellar Ataxias; Substantia Nigra; tau Proteins

The aggregation of α-synuclein (αS) in the central nervous system (CNS) is the hallmark of multiple system atrophy (MSA) and Lewy body diseases including Parkinson's disease (PD) and dementia with Lewy bodies (DLB) (α-synucleinopathies). To test the hypothesis that patients with α-synucleinopathies have a CNS environment favorable for αS aggregation, we examined the influence of cerebrospinal fluid (CSF) from patients with MSA (n=20), DLB (n=8), and PD (n=10) on in vitro αS fibril (fαS) formation at pH 7.5 and 37°C using fluorescence spectroscopy with thioflavin S, compared with those with hereditary spinocerebellar ataxia (hSCA) (n=16), and tension-type headache (n=7). CSF from MSA patients (MSA-CSF) promoted fαS formation more strongly than PD-, hSCA-, or headache-CSF. By electron microscopic analyses, the width of fαS formed in MSA-CSF was significantly greater than others. MSA may have a CSF environment particularly favorable for fαS formation.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Cerebrospinal Fluid; Female; Humans; Male; Middle Aged; Multiple System Atrophy; Nerve Degeneration; Neurofibrils; Spinocerebellar Ataxias; Tension-Type Headache

The cerebellar variant of multiple system atrophy (MSA-C) has overlapping clinical features with the hereditary spinocerebellar ataxias (SCAs), but can usually be distinguished on a clinical basis. We describe a patient who developed a sporadic, late-onset, rapidly progressive neurodegenerative disorder consistent with MSA-C. Genetic testing, however, showed an abnormal expansion of one allele of the spinocerebellar ataxia 3 (SCA3) gene. The clinical impression of MSA-C was confirmed by identification of numerous alpha-synuclein-containing glial cytoplasmic inclusions on autopsy. These findings suggest that abnormal expansion of the SCA3 gene may be a risk factor for the development of MSA-C.

Topics: Alleles; alpha-Synuclein; Ataxin-3; Autopsy; Cerebellum; DNA Repeat Expansion; Fatal Outcome; Female; Humans; Inclusion Bodies; Middle Aged; Multiple System Atrophy; Myelin Sheath; Nerve Degeneration; Nerve Tissue Proteins; Neuroglia; Nuclear Proteins; Point Mutation; Putamen; Repressor Proteins; Severity of Illness Index; Spinocerebellar Ataxias