The epigenetic mechanisms involved in mitochondrial dysfunction: Implication for Parkinson’s disease

Abstract

Mitochondrial dysfunction is one of the crucial factors involved in PD’s pathogenicity, which emerges from a combination of genetic and environmental factors. These factors cause differential molecular expression in neurons, such as varied transcriptional regulation of genes, elevated oxidative stress, α‐synuclein aggregation and endogenous neurotoxins release, which induces epigenetic modifications and triggers energy crisis by damaging mitochondria of the dopaminergic neurons (DN). So far, these events establish a complicated relationship with underlying mechanisms of mitochondrial anomalies in PD, which has remained unclear for years and made PD diagnosis and treatment extremely difficult. Therefore, in this review, we endeavored to discuss the complex association of epigenetic modifications and other associated vital factors in mitochondrial dysfunction. We propose a hypothesis that describes a vicious cycle in which mitochondrial dysfunction and oxidative stress act as a hub for regulating DA neuron's fate in PD. Oxidative stress triggers the release of endogenous neurotoxins (CTIQs) that lead to mitochondrial dysfunction along with abnormal α‐synuclein aggregation and epigenetic modifications. These disturbances further intensify oxidative stress and mitochondrial damage, amplifying the synthesis of CTIQs and works vice versa. This vicious cycle may result in the degeneration of DN to hallmark Parkinsonism. Furthermore, we have also highlighted various endogenous compounds and epigenetic marks (neurotoxic and neuroprotective), which may help for devising future diagnostic biomarkers and target specific drugs using novel PD management strategies.

Leucine‐rich repeat kinase 2 (LRRK2) inhibition upregulates microtubule‐associated protein 1B to ameliorate lysosomal dysfunction and parkinsonism

“…As previously reported, [35][36][37] sporadic PD accounts for approximately 85%-95% of all PD cases. It may result from a complex interplay of genetic susceptibility, environmental factors, age-related changes, oxidative stress, mitochondrial dysfunction, protein misfolding and aggregation, and neuroinflammation.…”

Targeting epigenetic modifications in Parkinson's disease therapy

“…In addition, the benzamide inhibitor chidamide was approved in China in 2017 for patients with PTCL. 20,50,153 Sodium butyrate (10) and its derivatives sodium phenylbutyrate (11) efficiently inhibit class I and II HDACs through the blood-brain barrier, protecting dopaminergic neurons from oxidative stress and α-syn toxicity. They both promote the expression of DJ-1 and neurotrophic factors GDNF and BDNF, which play a key role in neuronal growth, survival, and synaptic plasticity.…”

“…As an intricate neurological disease, the etiology of PD is still largely unknown, especially in terms of genetic, environmental, and aging factors. Growing consensus has been reached, however, that dysregulation of signaling pathways implicated in cell survival, mitochondrial dysfunction, apoptosis, autophagy, protein aggregation, oxidative damage, and neuroinflammation, contribute to its pathogenesis 9,10 . Current pharmacological treatments of PD are mainly based on three strategies to restore dopamine levels: (i) Increasing dopaminergic neurotransmission by the dopamine precursor levodopa (L‐DOPA); (ii) using dopaminergic agonists (amantadine/bromocriptine) to increase the availability of dopamine; (iii) inhibition of dopamine metabolism and reuptake by neighboring glial cells, by using monoamine‐oxidase B (MOB) inhibitors (rasagiline/selegiline) or catechol‐ O ‐methylatransferase (COMPT) inhibitors (entacapone/tolcapone) (Figure 1A).…”

Neurotoxicity and Underlying Mechanisms of Endogenous Neurotoxins

“…This process would further exacerbate oxidative stress and mitochondrial damage in the progress of PD. This hypothesis links the relationship between oxidative stress, endogenous neurotoxins, and mitochondrial dysfunction systematically [ 10 ].…”

“…The effects of endogenous neurotoxins on PD have been widely studied in literature and are highlighted in this review. The main pathological symptom of PD is the degeneration of dopaminergic neurons in the substantia nigra pars compact (SNpc), resulting in the loss of dopamine in the striatum and the formation of Lewy bodies (α-Synuclein protein inclusions) [ 10 , 11 ]. α-Synuclein is a 14kDa protein widely expressed in the mammalian brain.…”