Upregulation of cathepsin D in the caudate nucleus of primates with experimental parkinsonism

Abstract

BackgroundIn Parkinson's disease there is progressive loss of dopamine containing neurons in the substantia nigra pars compacta. The neuronal damage is not limited to the substantia nigra but progresses to other regions of brain, leading to loss of motor control as well as cognitive abnormalities. The purpose of this study was to examine causes of progressive damage in the caudate nucleus, which plays a major role in motor coordination and cognition, in experimental Parkinson's disease.ResultsUsing chronic 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine treatment of rhesus monkeys to model Parkinson's disease, we found a upregulation of Cathepsin D, a lysosomal aspartic protease, in the caudate nucleus of treated monkeys. Immunofluorescence analysis of caudate nucleus brain tissue showed that the number of lysosomes increased concurrently with the increase in Cathepsin D in neurons. In vitro overexpression of Cathepsin D in a human neuroblastoma cell line led to a significant increase in the number of the lysosomes. Such expression also resulted in extralysosomal Cathepsin D and was accompanied by significant neuronal death associated with caspase activation. We examined apoptotic markers and found a strong correlation of Cathepsin D overexpression to apoptosis.ConclusionsFollowing damage to the substantia nigra resulting in experimental Parkinson's disease, we have identified pathological changes in the caudate nucleus, a likely site of changes leading to the progression of disease. Cathepsin D, implicated in pathogenic mechanisms in other disorders, was increased, and our in vitro studies revealed its overexpression leads to cellular damage and death. This work provides important clues to the progression of Parkinson's, and provides a new target for strategies to ameliorate the progression of this disease.

Preliminary study of protein changes in trisomy 21 fetus by proteomics analysis in amniocyte

“…Interestingly, human cells were not proven to have any inhibitors of CTSD, excluding DNA fragments and its propeptide detached during activation . In vitro study showed that overexpression of CTSD led to a significant increase of the number of the lysosomes in human neuroblastoma cells, which resulted in extralysosomal CTSD and was accompanied by associated with caspase activation resulting in significant neuronal death . Our study was in agreement with Chen's study, who found that CTSD exhibited more than 1.5‐fold upregulation in male amniocytes rather than female amniocytes .…”

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“…In control cells, the punctate distribution of Cat D (green stain) and LAMP-2 (red stain) and their co-localization (r ϭ 0.825) upon the merge, resulting in yellow stained lyso- somes, is indicative of undamaged lysosomes/autolysosomes (Fig. 10A) as shown previously (69). Incubation with TAM enhanced the punctate fluorescence pattern of both Cat D and LAMP-2 and their co-localization (r ϭ 0.944) in the merge relative to the control (Fig.…”

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“…Results from a recent cell culture study showed that, similar to GCase, deficiency of cathepsin D leads to increased cell‐to‐cell transmission of α‐synuclein aggregates . Paradoxally, in vivo and in vitro studies have reported opposite effects, as the expression of cathepsin D was shown to be upregulated in the striatum of a monkey MPTP model of PD and in fibroblasts from PD patients with GBA mutations, respectively . Although cathepsin D was initially suggested to be the main protease involved in α‐synuclein degradation, a recent study argued this notion because cathepsin D generates amyloidogenic C‐terminal truncated species and therefore requires the assistance of other proteases .…”