LINGO-1 inhibits growth responses in the central nervous system and LINGO-1 expression is increased when nerve cells are exposed to injury. We have shown that LINGO-1 expression is increased in vulnerable substantia nigra neurons in Parkinson’s disease (PD) patients, and also in a pre-clinical model of PD caused by alpha-synuclein overexpression. We therefore propose LINGO-1 inhibition as a therapeutic target for PD. Blocking LINGO-1 activity in vitro enhances neurite outgrowth of dopamine neurons. Moreover, eliminating the LINGO-1 gene (knockout) or application of LINGO-1 inhibitors prevents dopamine neurons from dying in pre-clinical models of PD caused by oxidative stress. We will now test LINGO-1 inhibition in an additional pre-clinical model of PD caused by alpha-synuclein overexpression.
We will test the capacity of LINGO-1 inhibition to protect dopamine neurons from degeneration in a pre-clinical model of alpha-synucleinopathy. The clear genetic and neuropathological evidence for the role of alpha-synuclein in PD pathogenesis is the rationale for choosing this model. Our AAV-alpha-synucleinopathy model (using gene delivery of mutant alpha-synuclein) exhibits a slow pattern of degeneration of dopamine neurons, and we have shown that the cell death is preceded by several predegenerative changes, which we have characterized. We will inject AAV- alpha-synuclein into LINGO-1-deficient pre-clinical models, and we will determine at different time points (8 and 24 weeks after injection) whether inhibition of LINGO-1 prevents alpha-synuclein-induced pathological changes to dopamine neurotransmission and dopamine neuron number.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Given our previous pre-clinical studies showing extensive neuroprotection by LINGO-1 blockade in oxidative stress models of PD, it is anticipated that inhibition of LINGO-1 will protect dopamine neurons from alpha-synuclein-mediated neuronal damage and dysfunction. We expect that this study will validate LINGO-1 inhibition as an appropriate target for the next phase of pre-clinical studies and potential clinical application.
Upon successful completion of this project, we will learn whether LINGO-1 inhibition can prevent neurotransmission changes and degeneration of substantia nigra dopamine neurons in an experimental model of PD caused by alpha-synuclein overexpression.