Mitochondrial Dysfunction in Parkinson's Disease: A Contribution to Cognitive Impairment?

Abstract

Among the non-motor symptoms associated with Parkinson's disease (PD), cognitive impairment is one of the most common and disabling. It can occur either early or late during the disease, and it is heterogeneous in terms of its clinical manifestations, such as Subjective Cognitive Dysfunction (SCD), Mild Cognitive Impairment (MCI), and Parkinson's Disease Dementia (PDD). The aim of the present review is to delve deeper into the molecular mechanisms underlying cognitive decline in PD. This is extremely important to delineate the guidelines for the differential diagnosis and prognosis of the dysfunction, to identify the molecular and neuronal mechanisms involved, and to plan therapeutic strategies that can halt cognitive impairment progression. Specifically, the present review will discuss the pathogenetic mechanisms involved in the progression of cognitive impairment in PD, with attention to mitochondria and their contribution to synaptic dysfunction and neuronal deterioration in the brain regions responsible for non-motor manifestations of the disease.

Keywords: Parkinson’s disease; cognitive impairment; mitochondria; synaptic dysfunction; α-synuclein neurons.

Figure 1

Dopaminergic pathways involved in motor and non-motor symptoms in Parkinson’s Disease. (A) Dopaminergic cerebral connections and their involvement in the regulation of brain function in physiological and pathological conditions; (B) dopaminergic brain regions affected in motor and non-motor disorders associated with PD.

Figure 2

Relationship between α-syn aggregation and mitochondrial dysfunction as pathogenetic mechanism of neuroplasticity rearrangement. (A) The increased deposition of misfolded α-syn within the Lewy bodies (B) induces mitochondrial dysfunction in the soma and neurites of dopaminergic neurons, with (C) consequent alterations in synaptic communication and plasticity.