In recent years, epigenetic mechanisms have been implicated in the development of multifactorial diseases including neurodegenerative disorders. In Parkinson’s disease (PD), as a synucleinopathy, most studies focused on DNA methylation of SNCA gene coding alpha-synuclein but obtained results were rather contradictory. In another neurodegenerative synucleinopathy, multiple system atrophy (MSA), very few studies investigated the epigenetic regulation. This study included patients with PD (n = 82), patients with MSA (n = 24), and a control group (n = 50). In three groups, methylation levels of CpG and non-CpG sites in regulatory regions of the SNCA gene were analyzed. We revealed hypomethylation of CpG sites in the SNCA intron 1 in PD and hypermethylation of predominantly non-CpG sites in the SNCA promoter region in MSA. In PD patients, hypomethylation in the intron 1 was associated with earlier age at the disease onset. In MSA patients, hypermethylation in the promotor was associated with shorter disease duration (before examination). These results showed different patterns of the epigenetic regulation in two synucleinopathies—PD and MSA.

α-, β-, and γ-Synuclein are intrinsically disordered proteins implicated in physiological processes in the nervous system of vertebrates. α-synuclein (αSyn) is the amyloidogenic protein associated with Parkinson’s disease and certain other neurodegenerative disorders. Intensive research has focused on the mechanisms that cause αSyn to form amyloid structures, identifying its NAC region as being necessary and sufficient for amyloid assembly. Recent work has shown that a 7-residue sequence (P1) is necessary for αSyn amyloid formation. Although γ-synuclein (γSyn) is 55% identical in sequence to αSyn and its pathological deposits are also observed in association with neurodegenerative conditions, γSyn is resilient to amyloid formation in vitro. Here, we report a rare single nucleotide polymorphism (SNP) in the SNCG gene encoding γSyn, found in two patients with amyotrophic lateral sclerosis (ALS). The SNP results in the substitution of Met38 with Ile in the P1 region of the protein. These individuals also had a second, common and nonpathological, SNP in SNCG resulting in the substitution of Glu110 with Val. In vitro studies demonstrate that the Ile38 variant accelerates amyloid fibril assembly. Contrastingly, Val110 retards fibril assembly and mitigates the effect of Ile38. Substitution of residue 38 with Leu had little effect, while Val retards, and Ala increases the rate of amyloid formation. Ile38 γSyn also results in the formation of γSyn-containing inclusions in cells. The results show how a single point substitution can enhance amyloid formation of γSyn and highlight the P1 region in driving amyloid formation in another synuclein family member.

An intronic GAA repeat expansion in the FGF14 gene was recently identified as a common cause of autosomal dominant GAA-FGF14 ataxia (SCA27B). We aimed to characterize in detail the clinical and video-oculographic features in our cohort of SCA27B patients. We genotyped the FGF14 GAA repeat expansion in 52 patients with unsolved late-onset cerebellar ataxia. Brain MRI and nerve conduction study, as well as video-oculographic (VOG) assessment, were performed. Eight patients (15.4%) with pathogenic GAA repeat expansion in the FGF14 gene were found. The median age at onset was 51 years (range—23–63 years). Sensory axonal neuropathy was found in 5/8 patients. Cerebellar atrophy was observed in 5/8 patients, and in one case, pontocerebellar atrophy was found. All tested patients had impaired smooth pursuit, 5/6 patients had impaired vestibulo-ocular reflex suppression, nystagmus, and an increased number of square wave jerks, 4/6 patients had horizontal gaze-evoked nystagmus, 3/6 had spontaneous downbeat nystagmus, and 1/6 had an upbeat one. Video head impulse test gain was lower than 0.8 on both sides in 2/4 patients, along with the presence of overt saccades. Further studies in different cohorts are needed to complete the phenotype of the FGF14-related disorders.

ЦЕЛЬ ИССЛЕДОВАНИЯ Оценить частоту встречаемости спиноцеребеллярной атаксии 8-го типа (СЦА8) у пациентов с прогрессирующими мозжечковыми атаксиями, описать клинические особенности фенотипа у пациентов с СЦА8. МАТЕРИАЛ И МЕТОДЫ Генотипирование CTA/CTG-повторов в гене ATXN8OS проведено 411 пациентам с дегенеративными атаксиями методом фрагментного анализа. Предварительно были исключены СЦА 1, 2, 3 и 6-го типов, атаксия Фридрейха. Всем пациентам выполнена МРТ головного мозга, оценка по шкале для обследования и оценки атаксии (SARA), для скрининга когнитивных нарушений использовали Монреальскую шкалу оценки когнитивных функций. РЕЗУЛЬТАТЫ Выявлены 6 (1,5%) пациентов с СЦА8 — носители экспансии в гене ATXN8OS (91—152 CTA/CTG-повторов). Все случаи были спорадическими. Возраст дебюта варьировал от 14 до 42 лет. У всех пациентов отмечалась медленно прогрессирующая мозжечковая атаксия, глазодвигательные нарушения, дизартрия, пирамидный синдром, у двух больных — когнитивные нарушения. У одной пациентки клиническая картина соответствовала мультисистемной атрофии мозжечкового типа (атаксия, ортостатическая гипотензия, атрофия мозжечка и ствола мозга). МРТ головного мозга у всех пациентов выявила атрофию мозжечка. ЗАКЛЮЧЕНИЕ СЦА8 является редкой формой аутосомно-доминантной атаксии с преобладанием классического фенотипа. Все выявленные случаи СЦА8 были спорадическими, что необходимо учитывать при планировании генетического тестирования у пациентов с СЦА.

Parkinsons disease (PD) is one of the most common movement disorders. It is primarily diagnosed clinically. A correct diagnosis of PD in its early stages is important for the development of a pathogenic treatment, which necessitates a search for potential biomarkers of the disease. We evaluated the diagnostic value of several microRNAs and their relationship with the clinical characteristics of PD. The study included 70 PD patients and 40 healthy volunteers. We analyzed the expression of 15 microRNAs in blood leukocytes, which were selected based on literature data and modern concepts of molecular PD pathogenesis. All patients were evaluated using the Hoehn and Yahr scale, UPDRS, NMSQ, and PDQ-39. The data analysis revealed a statistically significant increase in the expression of miR-7-5p, miR-29c-3p, and miR-185-5p and a statistically significant decrease in the expression of miR-29a-3p and miR-30c-1-5p in leukocytes in PD. However, the altered microRNA profile was shown to have a moderate diagnostic value for PD diagnosis. MicroRNA expression changes were associated with the motor and non-motor phenotypic features of PD and administration of anti-Parkinsons drugs. Also, a relationship between some of the microRNAs studied and the duration and severity of PD was found, which may potentially be used to monitor disease progression.

Hereditary spastic paraplegia (HSP) and spinocerebellar ataxia (SCA) are heterogeneous groups of neurodegenerative disorders with the main clinical manifestations including progressive pyramidal syndrome and cerebellar ataxia. The differential diagnosis of these diseases is difficult owing to the significant genetic and phenotypic polymorphism. The use of massive parallel sequencing (MPS) technologies makes it possible to assess the genetic basis of specific clinical syndromes and to clarify the systematization of these overlapping phenotypes. We examined 70 patients with degenerative cerebellar ataxias who were admitted to the clinic with one of the suspected forms of SCA. Mutation screening included panel sequencing on the Illumina MiSeq platform. In the group of patients with SCA phenotypes, four individuals (5.7%) were identified—carriers of mutations in the HSP genes: SPG5—1 patient, SPG7—1 patient, and SPG11—2 patients. Seven mutations were identified: CYP7B1 (SPG5) gene—p.R63X and p.R486C mutations; SPG7 gene—c.1047dupC (p.G352Rfs*43) and splice site mutation c.1779+1G>T, which was described by us for the first time. Two patients with SPG11 carried a compound heterozygous nonsense mutation p.Q811X in the SPG11 gene; other mutations were c.7168dupC (p.P2390fs) and c.733_734del (p.M245fs). The presented data confirm the concept that HSP and SCA represent a single continuum of spinocerebellar degenerations with a significant phenotypic overlap. To verify the diagnosis in patients with cerebellar and pyramidal syndrome of degenerative genesis, MPS methods should be used.