Selective Vulnerability of Basal Ganglia: Insights into the Mechanisms of Bilateral Striatal Necrosis

Selective neuronal death in neurodegenerative disorders represents the final step of a cascade of events, including neuroinflammation, regional-specific reactive gliosis, changes of brain-blood barrier structure and functions, metabolic failure and mitochondrial energy impairment. Bilateral striatal necrosis is usually reported in inherited mitochondrial disorders, suggesting a pathogenetic role of the energy impairment by mitochondrial dysfunction. We investigated mechanisms of the selective striatal degeneration, comparing clinical findings of a patient with an acquired bilateral striatal necrosis and experimental data of a selective basal ganglia degenerative model in rats. In a 70-year-old patient affected by severe parkinsonian syndrome triggered by persistent metabolic acidosis, brain MRI revealed bilateral cystic-lacunar necrosis of basal ganglia. Immunohistochemistry of rat brain sections after single intraperitoneal administration (60 mg/kg) of the mitochondrial toxin 3-nitropropionic acid (3-NP) revealed (i) selective bilateral striatal necrotic/cavitary lesions, (ii) degeneration of striatal medium spiny neurons, (iii) evidence of synaptic and transcriptional dysfunction, and (iv) reactive gliosis (activated microglia and astrocytes) in the striatum. Our data provide an intriguing hypothesis for the selective neuronal degeneration in the striatum, claiming that selective mitochondrial energy impairment associated to loco-regional neuroinflammation and reactive gliosis might contribute to synaptic dysfunction and excitotoxicity that ultimately lead to neuronal degeneration.