Reduced vesicular storage of catecholamines causes progressive degeneration in the locus ceruleus.
Parkinson's disease (PD) is the most common neurodegenerative motor disease. Pathologically, PD is characterized by Lewy body deposition and subsequent death of dopamine neurons in the substantia nigra pars compacta. PD also consistently features degeneration of the locus ceruleus, the main source of norepinephrine in the central nervous system. We have previously reported a mouse model of dopaminergic neurodegeneration based on reduced expression of the vesicular monoamine transporter (VMAT2 LO). To determine if reduced vesicular storage can also cause noradrenergic degeneration, we examined indices of damage to the catecholaminergic systems in brain and cardiac tissue of VMAT2 LO mice. At two months of age, neurochemical analyses revealed substantial reductions in striatal dopamine (94%), cortical dopamine (57%) and norepinephrine (54%), as well as cardiac norepinephrine (97%). These losses were accompanied by increased conversion of dopamine and norepinephrine to their deaminated metabolites. VMAT2 LO mice exhibited loss of noradrenergic innervation in the cortex, as determined by norepinephrine transporter immunoreactivity and (3)H-nisoxetine binding. Using unbiased stereological techniques, we observed progressive degeneration in the locus ceruleus that preceded degeneration of the substantia nigra pars compacta. In contrast, the ventral tegmental area, which is spared in human PD, remained unaffected. The coordinate loss of dopamine and norepinephrine neurons in VMAT2 LO mice parallels the pattern of neurodegeneration that occurs in human PD, and demonstrates that insufficient catecholamine storage can cause spontaneous degeneration in susceptible neurons, underscoring cytosolic catecholamine catabolism as a determinant of neuronal susceptibility in PD. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.
['Taylor|Tonya N|TN|', 'Alter|Shawn P|SP|', 'Wang|Minzheng|M|', 'Goldstein|David S|DS|', 'Miller|Gary W|GW|']
D000818:Animals D002395:Catecholamines D002540:Cerebral Cortex D003342:Corpus Striatum D004298:Dopamine D005260:Female D008125:Locus Coeruleus D008297:Male D051379:Mice D008818:Mice, Neurologic Mutants D009206:Myocardium D009410:Nerve Degeneration D009638:Norepinephrine D050484:Norepinephrine Plasma Membrane Transport Proteins D010300:Parkinson Disease D050493:Vesicular Monoamine Transport Proteins
Locus ceruleus Locus ceruleus Parkinson's disease dopamine substantia nigra pars compacta Norepinephrine Norepinephrine VMAT2 norepinephrine transporter ventral tegmental area 3,4-dihydroxyphenylacetaldehyde 3,4-dihydroxyphenylacetic acid 3,4-dihydroxyphenylglycol 3-4-dihydroxyphenylglycolaldehyde DA DHPG DOPAC DOPAL DOPEGAL LC MAO NE NET SNpc TH VTA locus ceruleus monoamine oxidase norepinephrine tyrosine hydroxylase vesicular monoamine transporter 2