Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Rare genetic mutations in genes such as Parkin, Pink1, DJ-1, α-synuclein, LRRK2 and GBA are found to be responsible for the disease in about 15% of the cases. A key unanswered question in PD pathophysiology is why would these mutations, impacting basic cellular processes such as mitochondrial function and neurotransmission, lead to selective degeneration of SNc DA neurons? We previously showed in vitro that SNc DA neurons have an extremely high rate of mitochondrial oxidative phosphorylation and ATP production, characteristics that appear to be the result of their highly complex axonal arborization. To test the hypothesis in vivo that axon arborization size is a key determinant of vulnerability, we selectively labeled SNc or VTA DA neurons using floxed YFP viral injections in DAT-cre mice and showed that SNc DA neurons have a much more arborized axon than those of the VTA. To further enhance this difference, which may represent a limiting factor in the basal vulnerability of these neurons, we selectively deleted in mice the DA D2 receptor (D2-cKO), a key negative regulator of the axonal arbour of DA neurons. In these mice, SNc DA neurons have a 2-fold larger axonal arborization, release less DA and are more vulnerable to a 6-OHDA lesion, but not to α-synuclein overexpression when compared to control SNc DA neurons. This work adds to the accumulating evidence that the axonal arborization size of SNc DA neurons plays a key role in their vulnerability in the context of PD.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder primarily characterized by a massive loss of DA neurons in the substantia nigra pars compacta (SNc) that is thought to be accompanied by the loss of other types of neurons in a select subset of brain regions including the locus coeruleus and the pedunculopontine nucleus [1]
We found that in these mice, dopamine neurons in a region of the brain called the substantia nigra show increased vulnerability to a neurotoxin often used to model Parkinson’s disease in rodents
Our findings provide support for the hypothesis that the scale of a neuron’s connectivity directly influences its vulnerability to cellular stressors that trigger Parkinson’s disease
Summary
PD is a neurodegenerative disorder primarily characterized by a massive loss of DA neurons in the SNc that is thought to be accompanied by the loss of other types of neurons in a select subset of brain regions including the locus coeruleus and the pedunculopontine nucleus [1]. In the last few decades, many hypotheses have been raised about the core characteristics of SNc neurons that are responsible for their large bioenergetic requirements and that could explain their selective vulnerability These include, but are not limited to, pacemaking activity [2], high DA- and iron-related toxicity [3,4] and possessing a highly elaborate, long-range axonal arborization [5,6,7,8]. All these characteristics are thought to exert an important pressure on the capacity of these cells to efficiently produce energy and cope with the associated oxidative stress.
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