Abstract
Parkinson's disease (PD) is a neurodegenerative pathology whose molecular etiopathogenesis is not known. Novel contributions have come from familial forms of PD caused by alterations in genes with apparently unrelated physiological functions. The gene coding for alpha-synuclein (alpha-syn) (PARK1) has been investigated as alpha-syn is located in Lewy bodies (LB), intraneuronal inclusions in the substantia nigra (SN) of PD patients. A-syn has neuroprotective chaperone-like and antioxidant functions and is involved in dopamine storage and release. DJ-1 (PARK7), another family-PD-linked gene causing an autosomal recessive form of the pathology, shows antioxidant and chaperone-like activities too. The present study addressed the question whether alpha-syn and DJ-1 interact functionally, with a view to finding some mechanism linking DJ-1 inactivation and alpha-syn aggregation and toxicity. We developed an in vitro model of alpha-syn toxicity in the human neuroblastoma cell line SK-N-BE, influencing DJ-1 and alpha-syn intracellular concentrations by exogenous addition of the fusion proteins TAT-alpha-syn and TAT-DJ-1; DJ-1 was inactivated by the siRNA method. On a micromolar scale TAT-alpha-syn aggregated and triggered neurotoxicity, while on the nanomolar scale it was neuroprotective against oxidative stress (induced by H(2)O(2) or 6-hydroxydopamine). TAT-DJ-1 increased the expression of HSP70, while DJ-1 silencing made SK-N-BE cells more susceptible to oxidative challenge, rendering TAT-alpha-syn neurotoxic at nanomolar scale, with the appearance of TAT-alpha-syn aggregates. DJ-1 inactivation may thus promote alpha-syn aggregation and the related toxicity, and in this model HSP70 is involved in the antioxidant response and in the regulation of alpha-syn fibril formation.
Highlights
Parkinson’s disease (PD) is a neurodegenerative, multifactorial movement disorder affecting about 3% of the population over 65 years [1,2]
We analyzed a possible functional relationship between DJ-1 and a-syn in a cellular model of oxidative stress, a detrimental condition that is believed to play a major role in neurodegenerative disorders
DJ-1 role was investigated after increasing its intracellular expression level by exogenous addition of a TAT-fused recombinant protein, while its expression was downregulated by small-interfering RNAs (siRNA)
Summary
Parkinson’s disease (PD) is a neurodegenerative, multifactorial movement disorder affecting about 3% of the population over 65 years [1,2]. Genetic modifications in the proteins coded by the family-PD-linked genes PARK-1 [alias asynuclein (a-syn); GenBank: NM_000345; OMIM: #168600] and PARK-7 (alias DJ-1; GenBank: NM_007262; OMIM: #606324) cause respectively an autosomal dominant and an autosomal recessive form of PD [6,7,8,9]. Other data support an alternative scenario where a-syn aggregation prevents the protein performing its physiological neuroprotective functions that deal with chaperone-like activity, dopamine homeostasis and correct synaptic vesicular trafficking [17,18,19]. Novel contributions have come from familial forms of PD caused by alterations in genes with apparently unrelated physiological functions. DJ-1 (PARK7), another family-PD-linked gene causing an autosomal recessive form of the pathology, shows antioxidant and chaperone-like activities too
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