Parkinson disease, substantia nigra vulnerability, and calbindin expression: Enlightening the darkness?

Abstract

The selective death of different neuronal cell populations is a key feature of neurodegenerative diseases. Early in the evolution of Alzheimer’s disease, Parkinson’s disease (PD), Huntington disease, or spinocerebellar degeneration, for example, the affected neurons and the regional pattern of neuronal degeneration are relatively specific to each disorder and correlate fairly well with the clinical manifestations of each. In the case of PD, the cardinal features are intrinsically associated with selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and consequent striatal dopamine (DA) depletion. This cell loss follows a specific pattern of degeneration whereby the ventrolateral part of the SNc is the most affected. In contrast, the analogous neurons in the nearby dorsomedial and ventral tegmental areas are relatively resistant to degeneration. This differential vulnerability is observed regardless of disease etiology (sporadic or genetic) and is also observed in different PD animal models, indicating that some underlying differences must exist among different subgroups of dopaminergic neurons. This differential vulnerability has been associated with a plethora of mechanisms and features including physiological, neurochemical, and metabolic. The following may highlight the principal and more likely distinctive features underlying vulnerability of SNc neurons in PD: (1) anatomo-histological organization, namely, axonal arborization size, differential efferent and afferent connectivity, and neuronal size; (2) physiological profile, for example, different levels of cytosolic calcium (Ca) related to different expression of calcium channels (L-type 1.3) or higher basal rate of mitochondrial oxidative phosphorylation; (3) metabolic phenotype of dopaminergic neurons, neuromelanin production, neurotransmitter content (DA, glutamate), DA transporter (DAT), and vesicular monoamine transporter levels; (4) neurochemical features such GIRK2 and iron content; (5) developmental transcription factors (PITX3, NURR1, OTX2, ALDH1A1; for extensive recent reviews about vulnerability factors, see refs. 2-4). Calbindin (CB) is a calcium-binding protein that is widely expressed in many brain areas and is involved in regulation of intracellular Ca levels. The expression of CB has been implicated as a neuroprotective factor in several neurodegenerative disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, spinal muscular atrophy, and PD. CB is practically absent in the ventral tier of the SNc, whereas most dorsal tier SNc and ventral tegmental area dopaminergic neurons express CB. Thus, several studies have proposed CB as a marker to distinguish between neurons with different susceptibility to degeneration in PD. SNc dopaminergic neurons that express CB are selectively spared early in the evolution of PD and in monkeys mildly lesioned with 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP). In 1999, Damier and colleagues proposed a subdivision of the human SNc based on CB immunostaining, showing that the degree of neuronal loss in PD patients was significantly higher in the CBpoor pockets (nigrosomes) than in the CB-rich regions (matrix). However, earlier studies in rodents have produced some conflicting results. For instance, although the lack of SNc CB expression in knockout mice did not modify their sensitivity to MPTP intoxication, CB overexpression attenuated MPTP-induced nigrostriatal degeneration in transgenic mice. In this issue of Movement Disorders, Inoue and colleagues add an important piece of evidence to help understand the putative role of CB and neuronal vulnerability by demonstrating that viral vector-mediated CB recruitment into SNc dopaminergic neurons, especially those in the ventral tier of the nigra that do not normally contain CB, protects against MPTP in *Corresponding author: Javier Blesa, HM CINAC, Hospital Universitario HM Puerta del Sur, Mostoles, Spain; [email protected]