Fibroblast growth factor 21 and autophagy: A complex interplay in Parkinson disease

Abstract

Parkinson disease (PD) is a progressive and an age-dependent neurodegenerative disorder that predominantly affects the dopaminergic (DA) neuronal system in the substantia nigra (SN) region of the brain causing its deterioration over time. This deterioration gives rise to motor abnormalities in a PD affected patient causing tremor, bradykinesia, akinesia, postural instability, slurred speech etc. Recent research also enlightened that occurrence of non-motor dysfunctions in an individual initiate in the advanced stage of PD. It comprises mainly of cognitive dysfunction, constipation, sleep disorder, depression, anxiety etc. PD is known to affect at least 0.3% of the worldwide population and over 3% of those over 80 years of age. The predominant pathological hallmark of PD is aggregation of misfolded forms of alpha-synuclein (α-syn) in intraneuronal inclusions known as lewy bodies (LBs) in cell soma and in lewy neurites (LNs) in neuronal processes. α-syn is a presynaptic protein involved in neurotransmission. It is normally degraded by ubiquitin-proteasome system (UPS) and autophagy-lysosome system (ALS) [1]. UPS is responsible for the selective degradation of short-lived proteins and its dysfunction leads to the activation of ALS [2]. Exceptionally high affinities of the mutant forms of α-syn blocks the lysosomal uptake and inhibits its degradation via ALS [1]. This very well explains that ALS dysfunction is an important mechanism in neurodegeneration especially PD. Subsequently, blockage of ALS can aggravate various factors that can further complicate PD, the most important being endoplasmic reticulum (ER) stress [3]. ER stress is mainly a compensatory mechanism that is intended to preserve cellular function and neuronal survival [4] by activating PKR-like ER kinase (PERK), activating transcription factor(ATF)-6, inositol-requiring enzyme(IRE)-1 [5]. Phosphorylation of eukaryotic initiation factor 2-α (eIF2α), via activation by PERK, leads to translational induction of ATF4. Several studies have proved that stressors like starvation, autophagy dysfunction activates ATF4 which is also known to upregulate Fibroblast growth factor 21 (FGF21) [6].