Age-Dependent Dopaminergic Neurodegeneration and Impairment of the Autophagy-Lysosomal Pathway in LRRK-Deficient Mice

Abstract

LRRK2 mutations are the most common genetic cause of Parkinson's disease, but LRRK2's normal physiological role in the brain is unclear. Here, we show that inactivation of LRRK2 and its functional homolog LRRK1 results in earlier mortality and age-dependent, selective neurodegeneration. Loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and of noradrenergic neurons in the locus coeruleus is accompanied with increases in apoptosis, whereas the cerebral cortex and cerebellum are unaffected. Furthermore, selective age-dependent neurodegeneration is only present in LRRK^-/-, not LRRK1^-/- or LRRK2^-/- brains, and it is accompanied by increases in α-synuclein and impairment of the autophagy-lysosomal pathway. Quantitative electron microscopy (EM) analysis revealed age-dependent increases of autophagic vacuoles in the SNpc of LRRK^-/- mice before the onset of DA neuron loss. These findings revealed an essential role of LRRK in the survival of DA neurons and in the regulation of the autophagy-lysosomal pathway in the aging brain.

Keywords: LRRK1; LRRK2; Parkinson’s disease; apoptosis; autophagy; dopamine; dopaminergic neuron; neurodegeneration; ubiquitin; α-synuclein.