Interaction of Proteins Involved in Neuronal Proteinopathies.

Proteinopathy is characterized by the accumulation of aggregates of a specific protein in a target organ, tissue, or cell. The aggregation of the same protein can cause different pathologies as single protein can adopt various amyloidogenic, disease-specific conformations. The conformation governs the interaction of amyloid aggregates with other proteins that are prone to misfolding and, thus, determines disease-specific spectrum of concomitant pathologies. In this regard, a detailed description of amyloid protein conformation as well as spectrum of its interaction with other proteins become a key point for drafting of precise description of the disease. The majority of clinical cases of neuronal proteinopathies is caused by the aggregation of rather limited range of amyloidogenic proteins. Here, we provided the characterization of pathologies, related to the aggregation of amyloid ß peptide, tau protein, α-synuclein, TDP-43, and amylin, giving a short description of pathologies themselves, recent advances in elucidation of misfolded protein conformation, with emphasis on those protein aggregates extracted from biological samples, what is known about the interaction of this proteins, and the influence of this interaction on the progression of underlying disease and comorbidities.

Altered Sphingolipid Hydrolase Activities and Alpha-Synuclein Level in Late-Onset Schizophrenia.

Recent data described that patients with lysosomal storage disorders (LSDs) may have clinical schizophrenia (SCZ) features. Disruption of lipid metabolism in SCZ pathogenesis was found. Clinical features of schizophrenia (SCZ) have been demonstrated in patients with several lysosomal storage disorders (LSDs). Taking into account the critical role of lysosomal function for neuronal cells' lysosomal dysfunction could be proposed in SCZ pathogenesis. The current study analyzed lysosomal enzyme activities and the alpha-synuclein level in the blood of patients with late-onset SCZ. In total, 52 SCZ patients with late-onset SCZ, 180 sporadic Parkinson's disease (sPD) patients, and 176 controls were recruited. The enzymatic activity of enzymes associated with mucopolysaccharidosis (alpha-L-Iduronidase (IDUA)), glycogenosis (acid alpha-glucosidase (GAA)) and sphingolipidosis (galactosylceramidase (GALC), glucocerebrosidase (GCase), alpha-galactosidase (GLA), acid sphingomyelinase (ASMase)) and concentration of lysosphingolipids (hexosylsphingosine (HexSph), globotriaosylsphingosine (LysoGb3), and lysosphingomyelin (LysoSM)) were measured using LC-MS/MS. The alpha-synuclein level was estimated in magnetically separated CD45+ blood cells using the enzyme-linked immunosorbent assay (ELISA). Additionally, NGS analysis of 11 LSDs genes was conducted in 21 early-onset SCZ patients and 23 controls using the gene panel PGRNseq-NDD. Decreased ASMase, increased GLA activities, and increased HexSpn, LysoGb3, and LysoSM concentrations along with an accumulation of the alpha-synuclein level were observed in late-onset SCZ patients in comparison to the controls (p < 0.05). Four rare deleterious variants among LSDs genes causing mucopolysaccharidosis type I (IDUA (rs532731688, rs74385837) and type III (HGSNAT (rs766835582)) and sphingolipidosis (metachromatic leukodystrophy (ARSA (rs201251634)) were identified in five patients from the group of early-onset SCZ patients but not in the controls. Our findings supported the role of sphingolipid metabolism in SCZ pathogenesis. Aberrant enzyme activities and compounds of sphingolipids associated with ceramide metabolism may lead to accumulation of alpha-synuclein and may be critical in SCZ pathogenesis.

Development of molecular tools for diagnosis of Alzheimer's disease that are based on detection of amyloidogenic proteins.

Alzheimer's disease (AD) is the most common form of dementia that usually occurs among older people. AD results from neuronal degeneration that leads to the cognitive impairment and death. AD is incurable, typically develops over the course of many years and is accompanied by a loss of functional autonomy, making a patient completely dependent on family members and/or healthcare workers. Critical features of AD are pathological polymerization of Aß peptide and microtubule-associated protein tau, accompanied by alterations of their conformations and resulting in accumulation of cross-ß fibrils (amyloids) in human brains. AD apparently progresses asymptomatically for years or even decades before the appearance of symptoms. Therefore, development of the early AD diagnosis at a pre-symptomatic stage is essential for potential therapies. This review is focused on current and potential molecular tools (including non-invasive methods) that are based on detection of amyloidogenic proteins and can be applicable to early diagnosis of AD.Abbreviations: Aß - amyloid-ß peptide; AßO - amyloid-ß oligomers; AD - Alzheimer's disease; ADRDA - Alzheimer's Disease and Related Disorders Association; APH1 - anterior pharynx defective 1; APP - amyloid precursor protein; BACE1 - ß-site APP-cleaving enzyme 1; BBB - brain blood barrier; CJD - Creutzfeldt-Jakob disease; CRM - certified reference material; CSF - cerebrospinal fluid; ELISA - enzyme-linked immunosorbent assay; FGD - 18F-fluorodesoxyglucose (2-deoxy-2-[18F]fluoro-D-glucose); IP-MS - immunoprecipitation-mass spectrometry assay; MCI - mild cognitive impairment; MDS - multimer detection system; MRI - magnetic resonance imaging; NIA-AA - National Institute on Ageing and Alzheimer's Association; NINCDS - National Institute of Neurological and Communicative Disorders and Stroke; PEN2 - presenilin enhancer 2; PET - positron emission tomography; PiB - Pittsburgh Compound B; PiB-SUVR - PIB standardized uptake value ratio; PMCA - Protein Misfolding Cycling Amplification; PrP - Prion Protein; P-tau - hyperphosphorylated tau protein; RMP - reference measurement procedure; RT-QuIC - real-time quaking-induced conversion; SiMoA - single-molecule array; ThT - thioflavin T; TSEs - Transmissible Spongiform Encephslopathies; T-tau - total tau protein.