Conditional deletion of Ndufs4 in dopaminergic neurons promotes Parkinson’s disease-like non-motor symptoms without loss of dopamine neurons

Abstract

Reduction of mitochondrial complex I activity is one of the major hypotheses for dopaminergic neuron death in Parkinson’s disease. However, reduction of complex I activity in all cells or selectively in dopaminergic neurons via conditional deletion of the Ndufs4 gene, a subunit of the mitochondrial complex I, does not cause dopaminergic neuron death or motor impairment. Here, we investigated the effect of reduced complex I activity on non-motor symptoms associated with Parkinson’s disease using conditional knockout (cKO) mice in which Ndufs4 was selectively deleted in dopaminergic neurons (Ndufs4 cKO). This conditional deletion of Ndufs4, which reduces complex I activity in dopamine neurons, did not cause a significant loss of dopaminergic neurons in substantia nigra pars compacta (SNpc), and there was no loss of dopaminergic neurites in striatum or amygdala. However, Ndufs4 cKO mice had a reduced amount of dopamine in the brain compared to control mice. Furthermore, even though motor behavior were not affected, Ndufs4 cKO mice showed non-motor symptoms experienced by many Parkinson’s disease patients including impaired cognitive function and increased anxiety-like behavior. These data suggest that mitochondrial complex I dysfunction in dopaminergic neurons promotes non-motor symptoms of Parkinson’s disease and reduces dopamine content in the absence of dopamine neuron loss.

Loss of Mitochondrial Ndufs4 in Striatal Medium Spiny Neurons Mediates Progressive Motor Impairment in a Mouse Model of Leigh Syndrome

“…However, in MSN KO mice astrocytic mitochondrial function is likely spared. Finally, a recent study shows that Ndufs4 deletion in dopaminergic neurons causes Parkinson’s disease-like non-motor symptoms without neuronal loss, likely due to reduced dopamine brain levels (Choi et al, 2017 ). Hence, it is feasible that even though not sufficient to elicit neurodegeneration, lack of Ndufs4 may alter MSN function leading to behavioral deficits.…”

Calcium, Bioenergetics, and Parkinson’s Disease

“…However, drugs that effectively blunt the toxicity of these compounds have consistently failed in human clinical trials [ 249 , 250 , 251 ]. An influential paper on this topic demonstrated that impairing complex I function in DAergic neurons by deleting one of its subunits (Ndufs4) had little effect on them and did not alter the sensitivity to toxins like rotenone [ 252 , 253 , 254 , 255 ]. That said, making complex I insensitive to rotenone or MPTP by knocking down p13 confers neuroprotection in toxin models of PD [ 256 ].…”

Feeding difficulties, a key feature of the Drosophila NDUFS4 mitochondrial disease model

“…In fact, the NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 1 ( Ndufaf1 ) gene was found to be located in the interval of the anx gene and was downregulated in the anx/anx mice. Aside from these two models, one can find mentioned in the literature food provided ad libitum to facilitate the nutrition of weak animals, such as Ndufs4 −/− mice ( Alam et al, 2015 ; Choi et al, 2017 ; Karamanlidis et al, 2013 ; Kruse et al, 2008 ; Quintana et al, 2010 , 2012 ).…”