Parkinson’s disease: etiopathogenesis and treatment

Journal of Neurology Neurosurgery & Psychiatry, Journal Year: 2020, Volume and Issue: 91(8), P. 795 - 808

Published: June 23, 2020

The concept of ‘idiopathic’ Parkinson’s disease (PD) as a single entity has been challenged with the identification several clinical subtypes, pathogenic genes and putative causative environmental agents. In addition to classic motor symptoms, non-motor manifestations (such rapid eye movement sleep disorder, anosmia, constipation depression) appear at prodromic/premotor stage evolve, along cognitive impairment dysautonomia, progresses, often dominating advanced stages disease. key molecular mechanisms include α-synuclein misfolding aggregation, mitochondrial dysfunction, protein clearance (associated deficient ubiquitin-proteasome autophagy-lysosomal systems), neuroinflammation oxidative stress. involvement dopaminergic well noradrenergic, glutamatergic, serotonergic adenosine pathways provide insights into rich variable phenomenology associated PD possibility alternative therapeutic approaches beyond traditional dopamine replacement therapies. One biggest challenges in development potential neuroprotective therapies lack reliable sensitive biomarkers progression. Immunotherapies such use vaccination or monoclonal antibodies directed against aggregated, toxic α-synuclein.as anti-aggregation strategies are currently investigated trials. application glucagon-like peptide one receptor agonists, specific gene target agents GBA LRRK2 modifiers) other modifying drugs cautious optimism that more effective on horizon. Emerging therapies, new symptomatic drugs, innovative drug delivery systems novel surgical interventions give hope patients about their future outcomes prognosis.

Language: Английский

---

The genetics of Parkinson disease

Ageing Research Reviews, Journal Year: 2017, Volume and Issue: 42, P. 72 - 85

Published: Dec. 26, 2017

Language: Английский

---

Parkinson’s Disease

Medical Clinics of North America, Journal Year: 2018, Volume and Issue: 103(2), P. 337 - 350

Published: Dec. 3, 2018

Language: Английский

---

PINK1 and Parkin mitochondrial quality control: a source of regional vulnerability in Parkinson’s disease

Molecular Neurodegeneration, Journal Year: 2020, Volume and Issue: 15(1)

Published: March 13, 2020

Abstract That certain cell types in the central nervous system are more likely to undergo neurodegeneration Parkinson’s disease is a widely appreciated but poorly understood phenomenon. Many vulnerable subpopulations, including dopamine neurons substantia nigra pars compacta, have shared phenotype of large, distributed axonal networks, dense synaptic connections, and high basal levels neural activity. These features come at substantial bioenergetic cost, suggesting that these experience degree mitochondrial stress. In such context, mechanisms quality control play an especially important role maintaining neuronal survival. this review, we focus on understanding unique challenges faced by mitochondria summarize evidence dysfunction contributes pathogenesis death subpopulations. We then review mediated activation PINK1 Parkin, two genes carry mutations associated with autosomal recessive disease. conclude pinpointing critical gaps our knowledge Parkin function, propose connection between sporadic defects will lead us greater insights into question selective vulnerability.

Language: Английский

---

Parkinson disease and the immune system — associations, mechanisms and therapeutics

Nature Reviews Neurology, Journal Year: 2020, Volume and Issue: 16(6), P. 303 - 318

Published: April 24, 2020

Language: Английский

---

Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state

Brain, Journal Year: 2021, Volume and Issue: 145(3), P. 964 - 978

Published: Dec. 13, 2021

Idiopathic Parkinson's disease is characterized by a progressive loss of dopaminergic neurons, but the exact aetiology remains largely unknown. To date, research has mainly focused on nigral although recent studies suggest disease-related changes also in non-neuronal cells and midbrain regions beyond substantia nigra. While there some evidence for glial involvement disease, molecular mechanisms remain poorly understood. The aim this study was to characterize contribution all cell types pathology single-nuclei RNA sequencing assess type-specific risk using latest genome-wide association study. We profiled >41 000 transcriptomes post-mortem from six idiopathic patients five age-/sex-matched controls. validate our findings spatial context, we utilized immunolabelling same tissues. Moreover, analysed disease-associated enrichment genes with expression patterns. discovered neuronal cluster CADPS2 overexpression low TH levels, which exclusively present midbrains. Validation analyses laser-microdissected neurons that represents dysfunctional neurons. With regard cells, observed an increase microglia patients. were more amoeboid, indicating activated state. reduction oligodendrocyte numbers remaining being stress-induced upregulation S100B. variants associated glia- neuron-specific gene patterns cases. Furthermore, astrocytes presented disease-specific proliferation dysregulation related unfolded protein response cytokine signalling. reactive patient showed CD44 overexpression, revealed pro-inflammatory trajectory elevated levels IL1B, GPNMB HSP90AA1. Taken together, generated first dataset midbrain, highlights as well 'pan-glial' activation central mechanism movement disorder. This finding warrants further into inflammatory signalling immunomodulatory treatments disease.

Language: Английский

---

Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations

Movement Disorders, Journal Year: 2018, Volume and Issue: 33(5), P. 660 - 677

Published: April 11, 2018

ABSTRACT The greatest unmet therapeutic need in Parkinson's disease is the development of treatment that slows relentless progression neurodegenerative process. concept “disease modification” encompasses intervention types ranging from those designed to slow underlying degeneration treatments directed at regenerating or replacing lost neurons. To date all attempts develop effective disease‐modifying therapy have failed. Many reasons been proposed for these failures including our rudimentary understanding pathogenesis and assumption each targeted mechanisms apply most patients with same clinical diagnosis. Here we review aspects this broad field general concepts past challenges followed by a discussion approaches under following 4 categories: (1) α‐synuclein, (2) pathogenic distinct α‐synuclein (most also potentially triggered toxicity), (3) non‐ SNCA genetic subtypes “PD,” (4) possible interventions not directly influencing PD pathobiology. We emphasize are currently active highlight wide range important outstanding questions concerns will be considered advance modification PD. Critically, it unknown whether dysfunctional molecular pathways/organelles amenable occur sequential fashion across clinically affected individuals manifest differentially independent It there no “order disruption” applicable but, rather, “type dependent on factors, variability other causes heterogeneity Knowing when (early vs late), which (eg, synaptic transmission, endosomal sorting maturation, lysosomal degradation, mitochondrial biogenesis), whom (PD subtype) specific disrupted cell pathways truly versus compensatory even protective, considering use single combined (“cocktails”) putative therapies selectively target processes. Beyond current phase 2 3 studies underway evaluating oxidative stress (inosine), cytosolic Ca 2+ (isradipine), iron (deferiprone), extracellular (passive immunization), upcoming trials affecting c‐Abl, glucagon‐like peptide‐1, glucocerebrosidase, might argued further populations enriched process doomed repeat past. © 2018 International Parkinson Movement Disorder Society

Language: Английский

---

Targeting Alpha-Synuclein as a Therapy for Parkinson’s Disease

Frontiers in Molecular Neuroscience, Journal Year: 2019, Volume and Issue: 12

Published: Dec. 5, 2019

Parkinson's disease is one of the most common neurodegenerative disorders with a global burden approximately 6.1 million patients. Alpha-synuclein has been linked to both sporadic and familial forms disease. Moreover, alpha-synuclein present in Lewy-bodies, neuropathological hallmark disease, theis protein its aggregation have widely neurotoxic pathways that ultimately lead neurodegeneration. Such include autophagy/lysosomal dysregulation, synaptic dysfunction, mitochondrial disruption, endoplasmic reticulum oxidative stress. not only shown alter cellular pathways, but also spread between cells, causing host cells. Therapeutic approaches will need address several, if all, these angles toxicity. Here we review current advances therapeutic efforts for aim produce modifying therapy by targeting spread, production, aggregation, degradation alpha-synuclein. These include: receptor blocking strategies whereby putative receptors could be blocked inhibiting reduction which decrease amount available pathway use small molecules order target immunotherapy increase increasing flux. The research discussed here may tackles onset progression future.

Language: Английский

---

Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs

Nature Reviews Drug Discovery, Journal Year: 2018, Volume and Issue: 17(11), P. 804 - 822

Published: Sept. 28, 2018

Language: Английский

---

DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1

Proceedings of the National Academy of Sciences, Journal Year: 2019, Volume and Issue: 116(50), P. 25322 - 25328

Published: Nov. 25, 2019

Significance Endoplasmic reticulum (ER) and mitochondria form close associations that serve as a critical signaling platform. Loss-of-function mutations in DJ-1 are associated with autosomal recessive early onset Parkinson’s disease (PD). We found knockout caused significant impairments the structure function of ER-mitochondria association neuronal cells vivo. Reduced was deficits substantia nigra sporadic PD. Our study identifies component macrocomplex containing IP3R3-Grp75-VDAC1 at mitochondria-associated membrane playing an important role regulation integrity association. research offers insights into mechanism pathogenic deficiency

Language: Английский

---