Loss of PLA2G6 Function in INAD
Neurodegeneration with Brain Iron Accumulation (NBIA) is an inherited disorder where iron accumulates in the brain, resulting in Parkinsonism. One such form of NBIA is Infantile Neuroaxonal Dystrophy, or INAD. Symptoms of INAD typically begin in the first 1-2 years of life, and include progressive impaired movement, speech, and cognition. Mutations in the PLA2G6 gene have been identified in the majority of children with INAD, as well as in patients with dystonia parkinsonism, which typically has a later age of onset (15-50 years of age).
Our initial pathological characterization of an INAD case with confirmed PLA2G6 mutations has identified the accumulation of alpha-synuclein containing Lewy bodies and Lewy neurites, which is an important link to the defining pathological change in Parkinson disease. We have demonstrated that the human PLA2G6 protein, also known as calcium-independent phospholipase A2 beta, has both phospholipase and lysophospholipase activity, and that its catalytic activity is disrupted by INAD-associated mutations, but not mutations associated with dystonia-parkinonism. Additionally, mice with a targeted mutation in PLA2G6 exhibit features associated with INAD, including progressive neurological impairment and accumulation of ubiquitinated protein and membranous material in neuroaxonal spheroids. Ultimately, these findings provide the foundation for the development of therapeutic approaches in INAD, and current studies are underway to identify and test novel gene therapies and enzyme replacement therapies for disease alleviation.
- Engel LA, Jing Z, O'Brien DE, Sun M, Kotzbauer PT. (2010). Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia-parkinsonism. PLoS One. 5(9):e12897. PubMed PMID: 20886109.
- Malik I, Turk J, Mancuso DJ, Montier L, Wohltmann M, Wozniak DF, Schmidt RE, Gross RW, Kotzbauer PT. (2008). Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations. Am J Pathol. 172(2):406-416. PubMed PMID: 18202189.
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- Kotzbauer PT, Truax AC, Trojanowski JQ, Lee VM. (2005). Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2. J Neurosci. 25(3):689-698
Loss of PANK2 Function in NBIA
Another form of NBIA is Pantothenate Kinase-Associated Neurodegeneration (PKAN), which is caused by mutations in the PANK2 gene. Symptoms for this disease manifest between 3-13 years of age, and include difficulty walking, trouble chewing and swallowing, and speech problems.
While this form of NBIA is not a current focus in the lab, in the past we have produced new antibodies to the PANK2 protein that have shown that the protein is localized to neuronal mitochondria in the human brain, where it undergoes sequential proteolytic processing. PANK2 phosphorylates pantothenate (the initial step in CoA synthesis), and the catalytic activity of PANK2 is sensitive to feedback inhibition by CoA and acyl-CoAs. When we examined the effect of various PANK2 mutations on PANK2 catalytic activity, only some of the mutations resulted in a dramatic loss of catalytic activity, suggesting the possibility of other mechanisms leading to loss of function.
- Liang TW, Truax AC, Trojanowski JQ, Lee VM, Stern MB, Kotzbauer PT. (2006). Partial deficit of pantothenate kinase 2 catalytic activity in a case of tremor-predominant neurodegeneration with brain iron accumulation. Mov Disord. 21(5):718-722. PubMed PMID: 16450344.
- Kotzbauer PT, Truax AC, Trojanowski JQ, Lee VM. (2005). Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2. J Neurosci. 25(3):689-698. PubMed PMID: 15659606.