Parkinson's disease and mitophagy: an emerging role for LRRK2

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptoms such as tremor, slowness of movement and muscle stiffness. Its aetiology is poorly understood as the physiological and molecular mechanisms leading to this neuronal loss are currently unclear. However, mitochondrial and lysosomal dysfunction seem to play a central role in this disease. In recent years, defective mitochondrial elimination through autophagy, termed mitophagy, has emerged as a potential contributing factor to disease pathology. PINK1 and Parkin, two proteins mutated in familial PD, were found to eliminate mitochondria under distinct mitochondrial depolarisation-induced stress. However, PINK1 and Parkin are not essential for all types of mitophagy and such pathways occur in most cell types and tissues in vivo, even in the absence of overt mitochondrial stress — so-called basal mitophagy. The most common mutation in PD, that of glycine at position 2019 to serine in the protein kinase LRRK2, results in increased activity and this was recently shown to disrupt basal mitophagy in vivo. Thus, different modalities of mitophagy are affected by distinct proteins implicated in PD, suggesting impaired mitophagy may be a common denominator for the disease. In this short review, we discuss the current knowledge about the link between PD pathogenic mutations and mitophagy, with a particular focus on LRRK2.

Pharmacological rescue of impaired mitophagy in Parkinson’s disease-related LRRK2 G2019S knock-in mice

“…The mechanism by which LRRK2 kinase activity regulates basal mitophagy is currently unclear and various potential pathways exists, as discussed in our recent review ( Singh and Ganley, 2021 ). LRRK2 has been shown to phosphorylate a subset of Rab GTPases ( Steger et al, 2016 ) and, given the roles of Rabs in membrane trafficking, it is tempting to suggest that they may be key in regulating this mitophagy pathway ( Pfeffer, 2018 ; Pfeffer, 2017 ).…”

Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy

“…In PD, this has been driven by the understanding that two PD-associated genes PINK1 and PRKN combine to promote mitophagy and that this pathway is deficient in patients bearing loss-of-function mutations ( 28 ). Defects in mitochondria are also evident in idiopathic patients or those with mutations in other PD-associated genes such as LRRK2 (leucine-rich repeat kinase 2) ( 29 , 30 , 31 ). Furthermore, mitophagy is impaired in Alzheimer disease ( 32 , 33 ), and loss-of-function mutations in the mitophagy regulator TBK1 (TANK-binding kinase 1) and the receptor protein, optineurin, are associated with ALS (Amyotrophic Lateral Sclerosis) ( 34 ).…”

Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy

“…In Parkinson's disease this has been driven by the understanding that two Parkinson's associated genes PINK1 and Parkin combine to promote mitophagy and that this pathway is deficient in patients bearing loss of function mutations [28]. Defects in mitochondria are also evident in idiopathic patients or those with mutations in other PD associated genes such as LRRK2 [29][30][31]. Furthermore, mitophagy is impaired in Alzheimer's Disease [32,33] and loss of function mutations in the mitophagy regulator TBK1 and the adaptor protein, optineurin, are associated with Amyotrophic Lateral Sclerosis (ALS) [34].…”