The incidence of neurodegenerative diseases rises in parallel to the aging of human being, but the intricate relationship between aging and neurodegeneration (ND) remains extremely murky. We are exploring this relationship in Drosophila that lack or overexpress p35, a neuronal specific activator of the Cdk5 protein kinase. Deregulation of Cdk5 activity in humans has been associated with different neurological disorder such as Alzheimer’s and Parkinson’s, and either gain or loss of Cdk5 activity causes neurodegeneration in mouse models and neuronal loss in cultured mammalian neurons. We now describe a variety of clear neurodegeneration phenotypes in flies with altered expression of p35. Loss of dopaminergic (DA) neurons is the hallmark of Parkinson’s disease, and we find significant DA neuron loss in the brain of p35 deletion and over-expressing flies. DA neuron counting was done in the brains of 3, 10, 30 and 45 days old flies in control, a p35 deletion mutant and strains that overexpress p35 modestly (2.5-3x). No significant DA neuron loss was observed in control flies till the age of 30 days. However, p35 null and OE strains showed significant loss of neurons as early as 10days, with substantial loss by 30days, compared to the control. We also observed that the p35 mutant and OE strains were sensitive towards oxidative stress generator (H2O2 and paraquat). In case of H2O2 challenge median survival of p35 mutant and OE were 36 and 48 hrs respectively, which was 60 hrs for age matched (30 days) control. p35 mutant and OE strains also had higher level of reactive oxygen species in comparison to age- matched control (~1.5 and ~2.5x, respectively). Analysis of autophagy markers in the mutant brains revealed ~2.0x higher accumulation of Ref(2)P (homologue of mammalian p62) and similar increase in LC3 cleavage.The alteration in autophagy, is presumably linked to the ND, which we observed in our p35 gain- and loss-of-function models. Finally, we observed an early onset of impaired locomotor performance in the mutant and OE strains as compared to control flies. All the phenotypes described above in the p35 mutant were significantly rescued by inserting transposon carrying the genomic p35 locus, demonstrating the specificity of the phenotypes. These data suggest that analysis of the p35 model should be informative for unravelling the complex cellular endophenotypes associated with neurodegenerative disorders.