Recent Advances in the Treatment of Genetic Forms of Parkinson’s Disease: Hype or Hope?

Cells, Journal Year: 2023, Volume and Issue: 12(5), P. 764 - 764

Published: Feb. 27, 2023

Parkinson’s disease (PD) is a multifarious neurodegenerative disease. Its pathology characterized by prominent early death of dopaminergic neurons in the pars compacta substantia nigra and presence Lewy bodies with aggregated α-synuclein. Although α-synuclein pathological aggregation propagation, induced several factors, considered one most relevant hypotheses, PD pathogenesis still matter debate. Indeed, environmental factors genetic predisposition play an important role PD. Mutations associated high risk for PD, usually called monogenic underlie 5% to 10% all cases. However, this percentage tends increase over time because continuous identification new genes The variants that can cause or has also given researchers possibility explore personalized therapies. In narrative review, we discuss recent advances treatment forms focusing on different pathophysiologic aspects ongoing clinical trials.

Language: Английский

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Targeted protein degradation for the treatment of Parkinson’s disease: Advances and future perspective

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 166, P. 115408 - 115408

Published: Aug. 29, 2023

Parkinson's disease (PD) is a progressive disorder that belongs to class of neurodegenerative disorders (NDs) called Synucleinopathies. It has characterized by the misfolding and aggregation a-synuclein. Our understanding PD continues evolve, so does our approach treatment. including therapies aimed at delaying pathology, quitting neuronal loss, shortening course selectively targeting essential proteins suspected play role in pathogenesis. One emerging generating significant interest Targeted Protein Degradation (TPD). TPD an innovative method allows us specifically break down certain using specially designed molecules or peptides, like PROteolysis-TArgeting-Chimera (PROTACs). This holds great promise, particularly context NDs. In this review, we will briefly explain its pathogenesis, followed discussing protein degradation systems strategy reviewing synthesized small peptides. Finally, future perspectives challenges field are discussed.

Language: Английский

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The Effect of p.G2019S Mutation in the LRRK2 Gene on the Activity of Lysosomal Hydrolases and the Clinical Features of Parkinson's Disease Associated with p.N370S Mutation in the GBA1 Gene

Journal of Integrative Neuroscience, Journal Year: 2024, Volume and Issue: 23(1), P. 16 - 16

Published: Jan. 16, 2024

Background: Mutations in the glucocerebrosidase (GBA1) and leucine-rich repeat kinase 2 (LRRK2) genes, encoding lysosomal enzyme (GCase) (LRRK2), respectively, are most common related to Parkinson's disease (PD). Recent data suggest a possible functional interaction between GCase LRRK2 their involvement sphingolipid metabolism. The aim of present study was describe clinical course evaluate activities concentrations blood patients with PD associated dual mutations p.N370S GBA1 p.G2019S (p.N370S/GBA-p.G2019S/LRRK2-PD) as well asymptomatic mutation carriers (p.N370S/GBA1-p.G2019S/LRRK2-carrier). Methods: One patient p.N370S/GBA1-p.G2019S/LRRK2-PD one p.N370S/GBA1-p.G2019S/LRRK2-carrier were enrolled. GBA1-associated (GBA1-PD), LRRK2-associated (LRRK2-PD), sporadic (sPD) described earlier by our research group. A neuropsychiatric examination carried out using scales (Montreal Cognitive Assessment scale (MoCA), Mini-mental State Examination (MMSE), Frontal Batter (FAB), Hospital Anxiety, Depression Scale (HADS), etc). Lysosomal activity (GCase, alpha-galactosidase [GLA], acid sphingomyelinase [ASMase], galactosylcerebrosidase [GALC]) (hexasylsphingosine [HexSph], lysoglobotriaosylsphingosine [LysoGb3], lysosphingomyelin [LysoSM]) assessed high-performance liquid chromatography–tandem mass spectrometry blood. following comparison previously groups GBA1-PD sPD conducted. Results: Clinical features included an early age onset (46 years) mild cognitive affective disorders (MMSE = 29, MoCA 23), despite long (24 disease. Interestingly, no differences found hydrolase lysosphingolipid patients. However, lower these than LRRK2-PD, sPD, controls. Additionally, characterized pronounced decreased ASMase increased LysoSM concentration compared (p 0.023, p 0.027, respectively). Conclusions: Based on patient, results indicate protective effect gene p.N370S/GBA1-PD. identified alteration provide basis for further research.

Language: Английский

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Can We Treat Neurodegenerative Proteinopathies by Enhancing Protein Degradation?

Movement Disorders, Journal Year: 2022, Volume and Issue: 37(7), P. 1346 - 1359

Published: May 17, 2022

Abstract Neurodegenerative proteinopathies are defined as a class of neurodegenerative disorders, with either genetic or sporadic age‐related onset, characterized by the pathological accumulation aggregated protein deposits. These mainly include Alzheimer's disease (AD), Parkinson's (PD), amyotrophic lateral sclerosis (ALS), Huntington's (HD) well frontotemporal lobar degeneration (FTLD). The deposition abnormal aggregates in brain patients affected these disorders is thought to play causative role neuronal loss and progression. On that account, idea improving clearance has taken hold potential therapeutic strategy. Among possible approaches pursue for reducing accumulation, there stimulation main degradation machineries eukaryotic cells: ubiquitin proteasomal system (UPS) autophagy lysosomal pathway (ALP). Of note, several clinical trials testing efficacy UPS‐ ALP‐active compounds currently ongoing. Here, we discuss gaps controversies emerging from experimental studies assessing modulators UPS ALP proteinopathies, gather whether they may constitute real gateway disorders. © 2022 International Parkinson Movement Disorder Society.

Language: Английский

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Rotenone Blocks the Glucocerebrosidase Enzyme and Induces the Accumulation of Lysosomes and Autophagolysosomes Independently of LRRK2 Kinase in HEK-293 Cells

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(13), P. 10589 - 10589

Published: June 24, 2023

Parkinson’s disease (PD) is a neurodegenerative disorder caused by the progressive loss of dopaminergic (DAergic) neurons in substantia nigra and intraneuronal presence Lewy bodies (LBs), composed aggregates phosphorylated alpha-synuclein at residue Ser129 (p-Ser129α-Syn). Unfortunately, no curative treatment available yet. To aggravate matters further, etiopathogenesis still unresolved. However, neurotoxin rotenone (ROT) has been implicated PD. Therefore, it widely used to understand molecular mechanism neuronal cell death. In present investigation, we show that ROT induces two convergent pathways HEK-293 cells. First, generates H2O2, which, turn, either oxidizes stress sensor protein DJ-Cys106-SH into DJ-1Cys106SO3 or phosphorylation LRRK2 kinase Ser395 (p-Ser395 LRRK2). Once active, phosphorylates α-Syn (at Ser129), mitochondrial membrane potential (ΔΨm), triggers production cleaved caspase 3 (CC3), resulting signs apoptotic also reduces glucocerebrosidase (GCase) activity concomitant with accumulation lysosomes autophagolysosomes reflected increase LC3-II (microtubule-associated 1A/1B-light chain 3-phosphatidylethanolamine conjugate II) markers Second, exposure knockout (KO) cells displays an almost-normal phenotype. Indeed, KO showed neither DJ-1Cys106SO3, p-Ser395 LRRK2, p-Ser129α-Syn, nor CC3 but displayed high ΔΨm, reduced GCase activity, autophagolysosomes. Similar observations are obtained when wild-type (WT) exposed inhibitor conduritol-β-epoxide (CBE). Taken together, these imply combined development inhibitors compounds for recovering might be promising therapeutic agents

Language: Английский

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