alpha-synuclein and Syndrome

Genetic analysis has identified many loci designated as PARK loci (OMIM #168600). Many of these loci do not refer to idiopathic Parkinson's disease which is characterized by Lewy body pathology, but rather to clinical parkinsonisms. In this review, besides reviewing the genetic of the disorder, we argue that this designation is misleading and that if we seek to understand the pathogenesis, we should study the genetics of Lewy body diseases: these include not only idiopathic Parkinson's disease, but also such disparate syndromes as Hallevorden-Spatz disease and Niemann-Pick Type C.

Topics: alpha-Synuclein; F-Box Proteins; Genetic Predisposition to Disease; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lewy Body Disease; Mutation; Parkinson Disease; Protein Serine-Threonine Kinases; Syndrome; Ubiquitin-Protein Ligases

Neurodegenerative diseases are characterized by selective and progressive loss of specific populations of neurons, which determines the clinical presentation. The same neuronal populations can be affected in a number of different disorders. Given that the clinical presentation reflects the particular population of neurons that are targets of the disease process, it is clear that for any given clinical syndrome, more than one neurodegenerative disease can account for the clinical syndrome. Because of this clinical ambiguity, for the purpose of this brief review neurodegenerative disorders are classified according to the underlying molecular pathology rather than their clinical presentation. The major neurodegenerative diseases can be classified into amyloidoses, tauopathies, alpha-synucleinopathies and TDP-43 proteinopathies.

Topics: alpha-Synuclein; Amyloidosis; Gene Expression; Humans; Neurodegenerative Diseases; Neurons; Pathology, Molecular; Syndrome; Tauopathies; TDP-43 Proteinopathies

Inflammatory processes and mechanisms are of central importance in neurodegenerative diseases. In the brain, α-synucleinopathies such as Parkinson's disease (PD) and Lewy body dementia (LBD) show immune cytokine network activation and increased toll like receptor 3 (TLR3) levels for viral double-stranded RNA (dsRNA). Brain inflammatory reactions caused by TLR3 activation are also relevant to understand pathogenic cascades by viral SARS-CoV-2 infection causing post- COVID-19 brain-related syndromes. In the current study, following regional brain TLR3 activation induced by dsRNA in mice, an acute complement C3 response was seen at 2 days. A C3 splice-switching antisense oligonucleotide (ASO) that promotes the splicing of a non-productive C3 mRNA, prevented downstream cytokines, such as IL-6, and α-synuclein changes. This report is the first demonstration that α-synuclein increases occur downstream of complement C3 activation. Relevant to brain dysfunction, post-COVID-19 syndromes and pathological changes leading to PD and LBD, viral dsRNA TLR3 activation in the presence of C3 complement blockade further revealed significant interactions between complement systems, inflammatory cytokine networks and α-synuclein changes.

Topics: alpha-Synuclein; Animals; Brain; Complement C3; COVID-19; Cytokines; Lewy Body Disease; Mice; Parkinson Disease; RNA, Double-Stranded; SARS-CoV-2; Syndrome; Toll-Like Receptor 3

Topics: alpha-Synuclein; Amino Acids, Diamino; Amyotrophic Lateral Sclerosis; Animals; Bacterial Toxins; Causality; Cyanobacteria Toxins; Cycas; Dementia; Disease Models, Animal; Epidemiologic Research Design; Epidemiologic Studies; Flour; Guam; Hazardous Substances; Humans; Incidence; Indonesia; Japan; Marine Toxins; Methylazoxymethanol Acetate; Microcystins; Nerve Degeneration; Parkinsonian Disorders; Plant Extracts; Syndrome; Tauopathies

The motor and neuropsychological abnormalities in eight Greek patients with Parkinson's disease (PD) carrying the alpha-synuclein gene mutation (G209A) were studied. These patients (five men, three women) belonged to six different families. Their symptoms started between 32-50 years of age (mean +/- SD, 39.7 +/- 7.6 years) and they had a mean disease duration of 5.4 +/- 2.1 years (range, 2-9 years) at the time of examination. Rigidity and bradykinesia predominated both at disease onset as well as in the later stages and rest tremor was relatively uncommon. Neuropsychological assessment showed that one patient was mildly demented while another had impairment in memory, visuoconstructive abilities, and executive function. Depression was present in only one patient. Our findings indicate that genetic forms of parkinsonism share common motor and cognitive characteristics with sporadic PD but raise the possibility that greater cognitive impairment and the relative rarity of tremor may be distinctive features worthy of further investigation.

Topics: Adult; Age of Onset; alpha-Synuclein; Cognition Disorders; Diagnosis, Differential; Disease Progression; Female; Greece; Humans; Male; Middle Aged; Mutation; Nerve Tissue Proteins; Neuropsychological Tests; Parkinson Disease; Phenotype; Phosphoproteins; Syndrome; Synucleins