The Genetics of Parkinson’s Disease and Implications for Clinical Practice

Day, Jacob; Mullin, Stephen

doi:10.3390/genes12071006

Cited by 108 publications

(95 citation statements)

References 219 publications

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“…Among these, mutations in αSYN-encoding gene ( SNCA ), vacuolar protein sorting associated protein 35 ( VPS35 ), and leucine-rich repeat kinase 2 ( LRRK2 ) are the main causes of monogenic PD inherited in an autosomal dominant manner. There have also been identified autosomal-recessive cases of PD, mostly linked to mutations in PARK2 (encoding for Parkin), phosphatase and tensin homolog-induced putative kinase 1 ( PINK1 ) and PARK7 (encoding for DJ-1) genes [ 225 ].…”

Section: One-carbon Metabolism and Neurodegenerationmentioning

confidence: 99%

One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration

Lionaki

Ploumi

Tavernarakis

2022

Cells

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One-carbon metabolism (OCM) is a network of biochemical reactions delivering one-carbon units to various biosynthetic pathways. The folate cycle and methionine cycle are the two key modules of this network that regulate purine and thymidine synthesis, amino acid homeostasis, and epigenetic mechanisms. Intersection with the transsulfuration pathway supports glutathione production and regulation of the cellular redox state. Dietary intake of micronutrients, such as folates and amino acids, directly contributes to OCM, thereby adapting the cellular metabolic state to environmental inputs. The contribution of OCM to cellular proliferation during development and in adult proliferative tissues is well established. Nevertheless, accumulating evidence reveals the pivotal role of OCM in cellular homeostasis of non-proliferative tissues and in coordination of signaling cascades that regulate energy homeostasis and longevity. In this review, we summarize the current knowledge on OCM and related pathways and discuss how this metabolic network may impact longevity and neurodegeneration across species.

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Section: One-carbon Metabolism and Neurodegenerationmentioning

confidence: 99%

One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration

Lionaki

Ploumi

Tavernarakis

2022

Cells

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“…After AD, PD is the second most prevalent neurodegenerative disease worldwide and it is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra of the midbrain [ 100 ]. Most PD patients develop their clinical symptoms over the age of 60 and some cases can be caused by mutations in genes, including PRKN , SNCA and LRRK2 [ 101 , 102 ]. The significant loss of dopamine leads to classical idiopathic PD disease-like movement problems.…”

Section: Genetic Targeting Of the Csf-1r Or Treatment With Csf-1r Inh...mentioning

confidence: 99%

Inhibition of colony stimulating factor-1 receptor (CSF-1R) as a potential therapeutic strategy for neurodegenerative diseases: opportunities and challenges

Han

Chiţu

Stanley

et al. 2022

Cell. Mol. Life Sci.

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Microglia are specialized dynamic immune cells in the central nervous system (CNS) that plays a crucial role in brain homeostasis and in disease states. Persistent neuroinflammation is considered a hallmark of many neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson's disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) and primary progressive multiple sclerosis (MS). Colony stimulating factor 1-receptor (CSF-1R) is predominantly expressed on microglia and its expression is significantly increased in neurodegenerative diseases. Cumulative findings have indicated that CSF-1R inhibitors can have beneficial effects in preclinical neurodegenerative disease models. Research using CSF-1R inhibitors has now been extended into non-human primates and humans. This review article summarizes the most recent advances using CSF-1R inhibitors in different neurodegenerative conditions including AD, PD, HD, ALS and MS. Potential challenges for translating these findings into clinical practice are presented.

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“…The discovery of monogenic PD genes has led to in-depth insights into relevant disease mechanisms, broadening our molecular understanding of idiopathic PD [82]. Previously, mitochondrial dysfunction has already been implicated in idiopathic PD cases based on environmental studies [83].…”

Section: Treatment Strategiesmentioning

confidence: 99%

Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

Prasuhn

Brüggemann

2021

Preprint

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Background. Mitochondrial dysfunction has been identified as a pathophysiological hallmark of disease onset and progression in patients with Parkinsonian disorders. Besides the overall emergence of gene therapies in treating these patients, this highly relevant molecular concept has not yet been defined as a target for gene therapeutic approaches. Methods. This narrative review will discuss the experimental evidence suggesting mitochondrial dysfunction as a viable treatment target in patients with monogenic and idiopathic Parkinson’s disease. In addition, we will focus on general treatment strategies and crucial challenges which need to be overcome. Results. Our current understanding of mitochondrial biology in parkinsonian disorders opens up the avenue for viable treatment strategies in Parkinsonian disorders. Insights can be obtained from primary mitochondrial diseases. However, substantial knowledge gaps and unique challenges of mitochondria-targeted gene therapies need to be addressed to provide innovative treatments in the future. Conclusions. Mitochondria-targeted gene therapies are a potential strategy to improve an important primary disease mechanism in Parkinsonian disorders. However, further studies are needed to address the unique design challenges for mitochondria-targeted gene therapies.

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The Genetics of Parkinson’s Disease and Implications for Clinical Practice

Cited by 108 publications

References 219 publications

One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration

One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration

Inhibition of colony stimulating factor-1 receptor (CSF-1R) as a potential therapeutic strategy for neurodegenerative diseases: opportunities and challenges

Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

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