Sustained chemogenetic activation of locus coeruleus norepinephrine neurons promotes dopaminergic neuron survival in synucleinopathy.
Publication Year:
2022
PubMed ID:
35316276
Funding Grants:
Public Summary:
Parkinson’s disease causes movement problems mainly because certain brain cells that produce dopamine start to die. But other brain areas, like the locus coeruleus that makes a chemical called norepinephrine, also play a role in the disease.
This study looked at how activating norepinephrine-producing neurons affects Parkinson’s disease in mice. They found that these norepinephrine neurons connect directly to dopamine neurons and that increasing their activity helps protect dopamine neurons from dying. This also helped prevent movement problems in the mice.
Interestingly, this protection didn’t stop the build-up of harmful proteins or inflammation, meaning norepinephrine helps in a different way. In lab tests, norepinephrine helped dopamine neurons survive and grow.
Scientific Abstract:
Dopaminergic neuron degeneration in the midbrain plays a pivotal role in motor symptoms associated with Parkinson's disease. However, non-motor symptoms of Parkinson's disease and post-mortem histopathology confirm dysfunction in other brain areas, including the locus coeruleus and its associated neurotransmitter norepinephrine. Here, we investigate the role of central norepinephrine-producing neurons in Parkinson's disease by chronically stimulating catecholaminergic neurons in the locus coeruleus using chemogenetic manipulation. We show that norepinephrine neurons send complex axonal projections to the dopaminergic neurons in the substantia nigra, confirming physical communication between these regions. Furthermore, we demonstrate that increased activity of norepinephrine neurons is protective against dopaminergic neuronal depletion in human alpha-syn A53T missense mutation over-expressing mice and prevents motor dysfunction in these mice. Remarkably, elevated norepinephrine neurons action fails to alleviate alpha-synuclein aggregation and microgliosis in the substantia nigra suggesting the presence of an alternate neuroprotective mechanism. The beneficial effects of high norepinephrine neuron activity might be attributed to the action of norepinephrine on dopaminergic neurons, as recombinant norepinephrine treatment increased primary dopaminergic neuron cultures survival and neurite sprouting. Collectively, our results suggest a neuroprotective mechanism where noradrenergic neurons activity preserves the integrity of dopaminergic neurons, which prevents synucleinopathy-dependent loss of these cells.