Epidemiology reveals that type 2 diabetes is established in 8-30% of patients with Parkinson's disease and reports suggesting that up to 50-80% of patients with PD have abnormal glucose tolerance when tested.
As the pathogenesis of Parkinson's disease is gradually being elucidated the pathways involving mitochondrial turnover, neuroinflammation and aggregation of toxic protein oligomers all appear to be contributory. in particular mitochondrial dysfunction appears to play a fundamental role.
Mitochondrial dysfunction and role in insulin resistance:
• rates of ATP production reduced by 30% in the muscle of pre diabetic insulin resistant subjects
• ~1,5% of type 2 diabetes mellitus is attributable to the mitochondrial A3243G mutation(also cause of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes)
• the earliest sign of insulin resistance was shown to be reduction in expression of PGC1α (peroxisome proliferator activated receptor gamma coactivator 1 α) and the mitochondrial gene NRF1 (nuclear respiratory factor 1).
PGC1α is a transcriptional regulator of enzymes involved in mitochondrial respiration. Its expression is induced by physical exercise and reverts to baseline after cessation of exercise to enable fine control of the energy demands of skeletal muscle. Individuals that undergo regular exercise have chronically elevated levels of PGC1α, in association with a switch in muscle fiber type characterized by increased mitochondrial density and function.
Hypermethylation of PGC1α is found in association with reduced PGC1α messenger RNA and reduced mitochondrial DNA levels in subjects with type 2 diabetes mellitus. Hypermethylation of PGC1α can be caused by dietary factors such as fatty acids, as well as cytokines such as TNF-α. This suggests a potential mechanism underlying the gene–environment interaction in type 2 diabetes mellitus risk.
Mitochondrial dysfunction and Parkinson's disease:
• individuals injected with heroin contaminated with MPTP (1-methil 4-phenil 1,2,3,6-tetrahydropyridine) acutely develop parkinsonism.
MPTP and other environmental toxins cause degeneration of dopaminergic neuron in animal models by selective inhibition of complex I (NADH CoQ dehydrogenase).
• mitochondrial mutations have been associated with sporadic Parkinson's disease.
mitochondrial mutations can be induced by oxidative stress or ageing and it damages complex I and respiratory chain function through the production of reactive oxygen species. Normal human substantia nigra and striatum exhibit the greatest free radical-mediated mitochondrial damage with age.
• parkin mutations cause autosomal recessive juvenile parkinsonism. studies have revealed that the function of parkin is involved in monitoring the quality of mitochondria and trigger mitophagy of dysfunctional mitochondria.
• PINK1 (PTEN induced putative kinase 1) mutations cause autosomal recessive juvennile parkinsonism. it has been suggested that PINK1 recruits parkin from the cytoplasm to the mitochondria to initiate the process of mitophagy.
• DJ-1 is a protein present in the mitochondrial matrix and intermembrane space in peripheral tissue and parts of the brain. the deletion or silencing of DJ-1 causes parkinsonism probably by sensitising cells to oxidative stress. Its over-expression protects cells. knockout mice have increased sensitivity to MPTP and oxidative stress. DJ-1 associates with the mitochondrial Bcl-XL anti apoptotic protein.
• α-synuclein (SNCA) mutations can cause autosomal dominant PD and it is SNCA is the main component of the pathological features of the disease(the Lewy Body). the function of the protein is not fully understood but there are indications that SNCA affects various mitochondrial pathways: it is localized with cytocrome c forming hetero-oligomers, its fhosphorilated form(the prevalent form in Parkinson's disease) influences mitochondrial electron transport and its over-expression leads to the protein entering the mitochondria and interfering with the mitochondrial functions.
• leucine rich repeat kinase (LRRK-2) mutations can cause autosomal dominant PD. this protein has a GTPase and kinase domain and it appears to have an interaction with SNCA and study on the matter is still ongoing. however it has been demonstrated that transgenic mutant LRRK-2 mice have an ade dependent degeneration of dopamine nigrostriatal neurons and also damaged mitochondria and an increase in mitophagy.
• Glucocerebrosidase (GBA) mutations have been identified as a risk factor for PD even in the heterozygous state
It has been shown that SNCA inhibits the lysosomal activity of GBA and functional loss of GBA leads to accumulation of SNCA. This positive feedback loop explaines risk of Parkinson’s disease. Other potential mechanisms include lipid accumulation and anomalous mitophagy.
Neuroinflammation causes ulterior oxydative stress and damage to the mitochondria through the production of cytokines such as nitric oxide and TNF-α. and it is likely that multiple pathways remain relevant in parkinson's disease pathogenesis with interrelated aspects that impact on mitochondrial function.
Converging evidence implicating PGC1α:
PGC1α regulates nuclear and mitochondrial genes involved with mitochondrial biogenesis, respiration and metabolism of reactive oxygen species. insuline resistant paciens show a reduced expression of PGC1α and the mitochondrial encoded gene COX1. Polimorphisms of PGC1α has been associated with an increased risk for type 2 diabetes in diverse populations and reduction of PGC1α responsive genes has been shown among patients with type 2 diabetes and their asymptomatic relatives.
PGC1α also has a major role in Parkinson's disease pathogenesis. Many PGC1α responsive genes involved in mitochondrial electron transport, mitochondrial biogenesis, glucose utilization and glucose sensing were strongly associated with Parkinson's disease. Over-expression of PGC1α was able to protect dopamine cell loss induced by the mitochondrial toxin rotenone.
In parallel with these discoveries was the identification of parkin interacting substrate (PARIS) a zinc-finger protein which is up regulated in the substantia nigra of patients with not only parkin related parkinsonism but also sporadic PD. this up-regulation is both necessary and sufficient for the neurodegeneration associated with parkin in animal models. PARIS represses the expression of PGC1α and target genes and the site of interaction between PARIS and PGC1α is a sequence thet is involved in the regulation of insulin responsiveness and energy metabolism.
Conclusions
Loss of expression of PGC1α controlled genes in a common feature between abnormal mitochondrial function, Parkinson’s disease and abnormal glucose utilization which leads to type 2 diabetes. Hypermethylation of PGC1α may follow either genetic or environmental influences that promote accumulation of free fatty acids, TNF-α and ceramides, which leads to decompensation of mitochondrial bioenergetics and turnover and the onset of Parkinson’s disease. The fact that the substantia nigra pars compacta is more susceptible to energetic stress may be caused by the complexity and number of synapses and axon length and the substantia nigra have an incredibly complex structure from this point of view.
References:
Iciar et al. Parkinson's disease, insulin resistance and novel agents of neuroprotection. 2012;
Patti et al. Coordinated reduction of genes of oxidative damage in Parkin-deficent mice. 2003;
Lin et al. Metabolic control through the PGC-1 family of transcription coactivators. 2005;
Petersen et al. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes.2004
Shin et al. PARIS repression of PGC-1alpha contributes to neurodegeneration in Parkinson’s disease 2011;
Marius Manu
