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Protecting Innervation: Nmnat1 Gene Therapy for Parkinson's Disease

Axonal degeneration is a major pathological hallmark of Parkinson’s disease (PD). Evidence gathered in PD patients indicates that pathology in axons occurs prior to and independently of pathology seen in the cell body. Since inhibiting cell death does not also prevent axon loss, therapies only targeting the former fail to sustain function. This project will be the first to directly target axonal degeneration using the enzyme Nmnat1 in an attempt at preventing motor decline.

Project Description
We will express the enzyme Nmnat1 in the substantia nigra of a Parkinsonian pre-clinical model to determine whether Nmnat1 protects axons from degeneration that normally occurs with dopaminergic toxins in two different pre-clinical models. Using a battery of motor tests and unbiased cell counting procedures, we will determine whether Nmnat1 is an efficacious treatment for axonal pathology seen in Parkinson’s disease. 

Relevance to Diagnosis/Treatment of Parkinson’s Disease:  
Nigrostriatal axons in PD degenerate by a process called ‘dying back’ in which the part of the cell that connects to the striatum – the axon, dies first followed by progressive death of the diseased cell body. Most therapies currently being tested for PD focus on protecting the cell body and neglect degeneration that occurs in the axons. The success of this study will change the focus of existing therapies for PD in the direction of axonal degeneration.

Anticipated Outcome
The successful completion of this study will establish that preventing axonal degeneration in PD models is sufficient to prevent degeneration in the brain and prevent functional decline. This will confirm that merely targeting cell death in cell bodies is insufficient for reducing PD pathology. Since axonal pathology precedes cell death Nmnat1 therapy may be necessary as the primary course of action.


  • Jeffrey H. Kordower, PhD

    Chicago, IL United States

  • Jeffrey Millbrandt, MD, PhD

    St. Louis, MO United States

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