Regulation of neuronal bioenergetics as a therapeutic strategy in neurodegenerative diseases

Abstract

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a heterogeneous group of debilitating disorders with multifactorial etiologies and pathogeneses that manifest distinct molecular mechanisms and clinical manifestations with abnormal protein dynamics and impaired bioenergetics. Mitochondrial dysfunction is emerging as an important feature in the etiopathogenesis of these age-related neurodegenerative diseases. The prevalence and incidence of these diseases is on the rise with the increasing global population and average lifespan. Although many therapeutic approaches have been tested, there are currently no effective treatment routes for the prevention or cure of these diseases. We present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in these diseases and highlight recent advances in novel therapeutic strategies targeting neuronal bioenergetics as potential approach for treating these diseases.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; aging; amyotrophic lateral sclerosis; mitochondrial biogenesis; mitochondrial dysfunction; mtDNA mutations; neurodegeneration; oxidative stress.

Figure 1

Mitochondrial dysfunction is implicated in sporadic age-related NDDs. Of the multiple possible causes, mitochondrial impairments ranging from mitochondrial DNA (mtDNA) mutations, oxidative stress, altered gene expression, impaired mitobiogenesis, altered protein turnover and changed organelle dynamics (fission and fusion) are implicated. NDDs: Neurodegenerative diseases.

Figure 2

Schematic illustration of mitochondrial impairments observed in neurodegenerative diseases and potential therapeutic approaches for each level of deficiency. Possible causes of mitochondrial impairment are shown in red and potential therapeutic approaches are depicted in green. Optimal proteasome function and mitochondrial health are tightly interdependent.