The interplay of aging,genetics and environmental factors in the pathogenesis of Parkinson’s disease

Background:Parkinson’s disease(PD)is characterized by dopaminergic neuronal loss in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies(LB).During the course of disease,misfoldedα-synuclein,the major constituent of LB,spreads to different regions of the brain in a prion-like fashion,giving rise to successive non-motor and motor symptoms.Etiology is likely multifactorial,and involves interplay among aging,genetic susceptibility and environmental factors.Main body:The prevalence of PD rises exponentially with age,and aging is associated with impairment of cellular pathways which increases susceptibility of dopaminergic neurons to cell death.However,the majority of those over the age of 80 do not have PD,thus other factors in addition to aging are needed to cause disease.Discovery of neurotoxins which can result in parkinsonism led to efforts in identifying environmental factors which may influence PD risk.Nevertheless,the causality of most environmental factors is not conclusively established,and alternative explanations such as reverse causality and recall bias cannot be excluded.The lack of geographic clusters and conjugal cases also go against environmental toxins as a major cause of PD.Rare mutations as well as common variants in genes such as SNCA,LRRK2 and GBA are associated with risk of PD,but Mendelian causes collectively only account for 5%of PD and common polymorphisms are associated with small increase in PD risk.Heritability of PD has been estimated to be around 30%.Thus,aging,genetics and environmental factors each alone is rarely sufficient to cause PD for most patients.Conclusion:PD is a multifactorial disorder involving interplay of aging,genetics and environmental factors.This has implications on the development of appropriate animal models of PD which take all these factors into account.Common converging pathways likely include mitochondrial dysfunction,impaired autophagy,oxidative stress and neuroinflammation,which are associated with the accumulation and spread of misfoldedα-synuclein and neurodegeneration.Understanding the mechanisms involved in the initiation and progression of PD may lead to potential therapeutic targets to prevent PD or modify its course.

LRRK2, GBA and their interaction in the regulation of autophagy: implications on therapeutics in Parkinson’s disease

Mutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA) represent two most common genetic causes of Parkinson’s disease (PD). Both genes are important in the autophagic-lysosomal pathway (ALP), defects of which are associated with α-synuclein (α-syn) accumulation. LRRK2 regulates macroautophagy via activation of the mitogen activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) kinase (MEK) and the calcium-dependent adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathways. Phosphorylation of Rab GTPases by LRRK2 regulates lysosomal homeostasis and endosomal trafficking. Mutant LRRK2 impairs chaperone-mediated autophagy, resulting in α-syn binding and oligomerization on lysosomal membranes. Mutations in GBA reduce glucocerebrosidase (GCase) activity, leading to glucosylceramide accumulation, α-syn aggregation and broad autophagic abnormalities. LRRK2 and GBA influence each other: GCase activity is reduced in LRRK2 mutant cells, and LRRK2 kinase inhibition can alter GCase activity in GBA mutant cells. Clinically, LRRK2 G2019S mutation seems to modify the effects of GBA mutation, resulting in milder symptoms than those resulting from GBA mutation alone. However, dual mutation carriers have an increased risk of PD and earlier age of onset compared with single mutation carriers, suggesting an additive deleterious effect on the initiation of PD pathogenic processes. Crosstalk between LRRK2 and GBA in PD exists, but its exact mechanism is unclear. Drugs that inhibit LRRK2 kinase or activate GCase are showing efficacy in pre-clinical models. Since LRRK2 kinase and GCase activities are also altered in idiopathic PD (iPD), it remains to be seen if these drugs will be useful in disease modification of iPD.

The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies:a review

The clinical diagnosis of neurodegenerative disorders based on phenotype is difficult in heterogeneous conditions with overlapping symptoms.It does not take into account the disease etiology or the highly variable clinical course even amongst patients diagnosed with the same disorder.The advent of next generation sequencing(NGS)has allowed for a system-wide,unbiased approach to identify all gene variants in the genome simultaneously.With the plethora of new genes being identified,genetic rather than phenotype-based classification of Mendelian diseases such as spinocerebellar ataxia(SCA),hereditary spastic paraplegia(HSP)and Charcot-Marie-Tooth disease(CMT)has become widely accepted.It has also become clear that gene variants play a role in common and predominantly sporadic neurodegenerative diseases such as Parkinson’s disease(PD)and amyotrophic lateral sclerosis(ALS).The observation of pleiotropy has emerged,with mutations in the same gene giving rise to diverse phenotypes,which further increases the complexity of phenotype-genotype correlation.Possible mechanisms of pleiotropy include different downstream effects of different mutations in the same gene,presence of modifier genes,and oligogenic inheritance.Future directions include development of bioinformatics tools and establishment of more extensive public genotype/phenotype databases to better distinguish deleterious gene variants from benign polymorphisms,translation of genetic findings into pathogenic mechanisms through in-vitro and in-vivo studies,and ultimately finding disease-modifying therapies for neurodegenerative disorders.

LRRK2 mutant knock-in mouse models: therapeutic relevance in Parkinson’s disease

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are one of the most frequent genetic causes of both familial and sporadic Parkinson’s disease (PD). Mounting evidence has demonstrated pathological similarities between LRRK2-associated PD (LRRK2-PD) and sporadic PD, suggesting that LRRK2 is a potential disease modulator and a thera-peutic target in PD. LRRK2 mutant knock-in (KI) mouse models display subtle alterations in pathological aspects that mirror early-stage PD, including increased susceptibility of nigrostriatal neurotransmission, development of motor and non-motor symptoms, mitochondrial and autophagy-lysosomal defects and synucleinopathies. This review provides a rationale for the use of LRRK2 KI mice to investigate the LRRK2-mediated pathogenesis of PD and implications from current findings from different LRRK2 KI mouse models, and ultimately discusses the therapeutic potentials against LRRK2-associated pathologies in PD.