CHARACTERIZING THE EXPRESSION AND FUNCTION OF MESENCEPHALIC ASTROCYTE-DERIVED NEUROTROPHIC FACTOR IN CAENORHABDITIS ELEGANS

Abstract

Neurotrophic factors are proteins involved in the maturation, differentiation and survival of neurons. Due to their neuroprotective properties, they have been regarded as potent candidates for the treatment of neurodegenerative diseases. Recently, a novel family of neurotrophic factors was discovered comprising mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF). These factors have been shown to protect against the degeneration of nigrostriatal dopaminergic neurons in mammalian models of Parkinson's disease, however their neuroprotective mechanisms of action are not yet understood. Although distinct in vertebrates, MANF and CDNF constitute a single homolog in invertebrates. In the present study, we have characterized the in vivo expression and function of the C. elegans homolog manf-1. We have shown that manf-1 is not essential for neuronal development, however when knocked down, mutants exhibit enhanced age-related dopaminergic neuronal degeneration accompanied by an increase in the endogenous ER stress response. Loss of manf-1 function also results in enhanced alpha-synuclein expression and aggregation, a pathological hallmark of Parkinson’s disease.