Parkinson′s disease (PD) is the second most common neurodegenerative disorder after Alzheimer′s disease, affecting more than 6 million people worldwide. PD is a slowly progressing motor system neurodegeneration characterized by akinesia, rigidity and resting tremor. Neuropathologically PD is characterized by loss of dopaminergic cell bodies in the substantia nigra, resulting in a reduced supply of dopamine to the basal ganglia. The high metabolic rate of the substantia nigra combined with high content of oxidizable species and iron, high levels of reactive oxygen species (ROS) and low level of antioxidants, all serve to initiate and propagate apoptosis of the dopaminergic neurons.
Mutations in the α-synuclein gene (SNCA) occur in familial cases of Parkinson′s disease, pointing to a role for this gene in PD. α-Synuclein can form protein aggregates with additional cytoskeletal proteins including synaptophysin (SYP) and Tau (MAPT), which are believed to lead to the pathogenesis of Lewy body formation.
Synphilin (SNCAIP) interacts with α-synuclein in neuronal tissue and is thought to play a role in the formation of cytoplasmic inclusions and neurodegeneration. A mutation in this gene has been associated with Parkinson′s disease.
Mutations in the LRRK2 (PARK8) gene are found in about 5-6 percent of all familial cases as well as 2 percent of cases with no known cause. Interestingly, this mutation can cause early-onset Parkinson′s in families from diverse ethnic backgrounds, in a form that is identical in clinical symptoms to late-onset Parkinson′s. LRRK2 encodes a protein that is part of a larger multidomain protein with characteristic GTPase and kinase domains. LRRK2′s substrates, its binding partners and its regulators have yet to be confirmed or clarified, and consequently its role in normal physiological functions in the cell and in disease are still largely unknown.
Loss of function mutations in the Parkin (PARK2), PINK1 (PARK6) and PARK7 (DJ-1) genes resulting in functionally inactive proteins, underlie common forms of autosomal-recessive PD. Patients with loss-of-function parkin mutations account for an estimated 40-50 percent of all familial early-onset cases of PD, whereas mutations in PINK1 and PARK7 are less common. Several studies have demonstrated that products of all three recessive genes preserve mitochondrial functions, protect against reactive oxygen species, or play a role in protein degradation pathways. Normally, Parkin tags proteins with ubiquitin for degradation via the proteasome. Mutations in the Parkin gene lead to a loss of this activity. DJ-1 is a molecular chaperone involved in protein folding, as well as in other functions. It is found in the cytosol, the mitochondrial matrix and intermembrane space. It regulates redox-dependent signaling pathways and acts as a regulator of antioxidant gene expression.
UCHL1 (PARK5) is a member of the ubiquitin-C-terminal hydrolases. Expression of UCHL1 is highly specific to neurons and to cells of the diffuse neuroendocrine system and their tumors. A point mutation I93M in this protein is implicated as the cause of PD. Furthermore, a polymorphism S18Y in this gene has been found to be associated with a reduced risk for Parkinson′s disease. UCH-L1 is also associated with the Alzheimer′s disease.
The ATP13A2 (PARK9) gene encodes a member of the P5 subfamily of ATPases which transports inorganic cations as well as other substrates. Mutations in this gene are associated with Kufor-Rakeb syndrome (KRS), also referred to as Parkinson disease 9, and in juvenile forms of PD.
Additional genes, including GIGYF2 (PARK11), HTRA2 (OMI, PARK13) PLA2G6 (PARK14), FBXO7 (PARK15), STUB1 (CHIP) and RNF19A (Dorfin) are thought to be implicated in PD.
With its complex etiology and impact on millions, Parkinson′s Disease continues to be the subject of intensive research effort.