Fight Aging!

Parkinson's disease, like dementia with Lewy bodies, is a synucleinopathy, a condition characterized by the buildup of aggregates of misfolded, toxic α-synuclein that cause cell death in the brain. The mix of age-related cellular damage, evolved reactions to that damage, and individual genetic variance that leads to the creation of these aggregates is highly complex and poorly understood. As for other diseases involving forms of protein aggregate that harm tissues, such as the varied forms of amyloidosis, one possible shortcut to meaningful treatment is to clear the aggregates on a regular basis. The research community is making some inroads in this direction, such as the production of immunotherapies that can target misfolded proteins, but it has been slow going so far:

Accumulation and misfolding of the α-synuclein protein are core mechanisms in the pathogenesis of Parkinson's disease. While the normal function of alpha-synuclein is mainly related to the control of vesicular neurotransmission, its pathogenic effects are linked to various cellular functions, which include mitochondrial activity, as well as proteasome and autophagic degradation of proteins. Remarkably, these functions are also affected when the renewal of macromolecules and organelles becomes impaired during the normal aging process. As aging is considered a major risk factor for Parkinson's disease, it is critical to explore its molecular and cellular implications in the context of the alpha-synuclein pathology.

Ninety percent of all diagnosed Parkinson's disease cases have a multifactorial origin, which is likely to combine genetic and environmental components. Changes in the expression level and folding state of the α-syn protein, combined with the formation of various α-syn multimeric species, define the transition towards pathological conditions. Although it is recognized that aging is a major risk factor for Parkinson's disease, the time-dependent molecular changes that underlie the development of the pathology are only partially understood. Rationally, pathways implicated in protein and organelle recycling by the proteasome and autophagy, as well as the biogenesis and quality control of mitochondria are gaining attention, because they are critically affected both in Parkinson's disease and aging. In neurons exposed to the combined effects of α-syn and aging, these cellular mechanisms may undergo vicious circles precipitating neuronal demise.

However, compared to normal aging, Parkinson's disease pathology has clear specificities showing that this process cannot be merely considered as a form of accelerated aging. Therefore, it is critical to explore the effect of the α-syn pathology in the context of the neurons that are selectively vulnerable to the converging effects of aging and α-syn proteotoxicity. In particular, the morphology and the metabolic needs of dopamine neurotransmission, are critical factors for α-syn to exert its toxic effects. Using animal models dedicated to the study of the aging process, it will be important to understand the interaction between aging and α-syn in nigral dopaminergic neurons. By identifying therapeutic targets in this context, disease-modifying treatments may be found, that could be applicable to a broad population of patients.

Link: http://dx.doi.org/10.3390/biom5042675