Lysosomal function in macromolecular homeostasis and bioenergetics in Parkinson's disease

Abstract

The pathological changes occurring in Parkinson's and several other neurodegenerative diseases are complex and poorly understood, but all clearly involve protein aggregation. Also frequently appearing in neurodegeneration is mitochondrial dysfunction which may precede, coincide or follow protein aggregation. These observations led to the concept that protein aggregation and mitochondrial dysfunction either arise from the same etiological factors or are interactive. Understanding the mechanisms and regulation of processes that lead to protein aggregation or mitochondrial dysfunction may therefore contribute to the design of better therapeutics. Clearance of protein aggregates and dysfunctional organelles is dependent on macroautophagy which is the process through which aged or damaged proteins and organelles are first degraded by the lysosome and then recycled. The macroautophagy-lysosomal pathway is essential for maintaining protein and energy homeostasis. Not surprisingly, failure of the lysosomal system has been implicated in diseases that have features of protein aggregation and mitochondrial dysfunction. This review summarizes 3 major topics: 1) the current understanding of Parkinson's disease pathogenesis in terms of accumulation of damaged proteins and reduction of cellular bioenergetics; 2) evolving insights into lysosomal function and biogenesis and the accumulating evidence that lysosomal dysfunction may cause or exacerbate Parkinsonian pathology and finally 3) the possibility that enhancing lysosomal function may provide a disease modifying therapy.

Figure 1

Lysosomal deficiencies that may lead to neurodegeneration. Functions of lysosomes are regulated at multiple levels, including coordinated transcriptional regulation of lysosomal genes, trafficking of lysosomal proteins to the lysosomes, and proper function of the lysosomal membrane proteins and luminal acid hydrolases. Deficiencies of any of these processes may lead to deficiencies of reduced lysosomal degradation of aged or toxic proteins. The lysosomal substrate accumulation may in turn result in lysosomal expansion and storage and further disruption of its activities. Accumulation of aged, toxic or aggregated proteins and organelles, and accumulation of autophagosomes may lead to eventual neurodegeneration.

Figure 2

Consequence of Cathepsin D deficiencies. Cathepsin D is a major proteolytic enzyme in the lysosome. It cleaves α-synuclein in vitro and in cultured cells. Cathepsin D deficiency in human patients led to accumulation of lipofuscin and a prototype lysosomal storage disorder. Cathepsin D deficient worms, flies, mice, sheep and human patients exhibit increased α-synuclein accumulation and toxicity. Other associated cellular dysfunctions include: accumulation of autophagosomes, increased levels of Atg7, UCHL1, Park2, Cathepsin B, L, F, and H mRNAs, increased GAPDH and MEF2D proteins, impairment of proteasomal activities, and accumulation of ubiquitinated proteins. Overexpression of Cathepsin D in worms, flies, and mammalian cells has been shown to reduce α-synuclein aggregation and toxicity, suggesting a new approach to design future effective therapies.