Abstract
Small heat shock proteins (HSPs), such as HSP27, are ubiquitously expressed molecular chaperones and are essential for cellular homeostasis. The major functions of HSP27 include chaperoning misfolded or unfolded polypeptides and protecting cells from toxic stress. Dysregulation of stress proteins is associated with many human diseases including neurodegenerative diseases, such as Parkinson’s disease (PD). PD is characterized by the presence of aggregates of α-synuclein in the central and peripheral nervous system, which induces the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and in the autonomic nervous system. Autonomic dysfunction is an important non-motor phenotype of PD, which includes cardiovascular dysregulation, among others. Nowadays, the therapies for PD focus on dopamine (DA) replacement. However, certain non-motor symptoms with a great impact on quality of life do not respond to dopaminergic drugs; therefore, the development and testing of new treatments for non-motor symptoms of PD remain a priority. Since small HSP27 was shown to prevent α-synuclein aggregation and cytotoxicity, this protein might constitute a suitable target to prevent or delay the motor and non-motor symptoms of PD. In the first part of our review, we focus on the cardiovascular dysregulation observed in PD patients. In the second part, we present data on the possible role of HSP27 in preventing the accumulation of amyloid fibrils and aggregated forms of α-synuclein. We also include our own studies, highlighting the possible protective cardiac effects induced by L-DOPA treatment through the enhancement of HSP27 levels and activity.
Highlights
Heat shock proteins (HSPs) are a family of proteins produced by the cells of both unicellular and multicellular organisms when they are in different stressful situations in which upregulation of their transcription is shown as a part of the heat shock response [1].HSPs are highly conserved in the evolutionary history of all living beings, since they appear in all organisms, from bacteria to humans
There is growing evidence that HSP27 is involved in the cellular response to protein aggregation in a variety of neurodegenerative diseases, and the intra- or extra-aggregation of specific proteins to form amyloid fibrils is a pathological hallmark of neurodegenerative diseases, such as Parkinson’s disease (PD) [72]. α-synuclein is one example of a protein that forms fibrils and insoluble deposits both in vitro and in vivo, being highly expressed in multiple rethe proteasome [68]
There is growing evidence that HSP27 is involved in the cellular response to protein aggregation in a variety of neurodegenerative diseases, and the intra- or extra-aggregation of specific proteins to form amyloid fibrils is a pathological hallmark of neurodegenerative diseases, such as PD [72]. α-synuclein is one example of a protein that forms fibrils and insoluble deposits both in vitro and in vivo, being highly expressed in multiple regions of the brain, mainly in dopaminergic neurons in the substantia nigra pars compacta (SNpc) of PD patients [73]
Summary
Heat shock proteins (HSPs) are a family of proteins produced by the cells of both unicellular and multicellular organisms when they are in different stressful situations in which upregulation of their transcription is shown as a part of the heat shock response [1]. HSPs act as molecular chaperones with different functions: (a) promoting correct folding of proteins that cannot reach or maintain their active conformation and, avoiding inappropriate interactions, reducing the formation of irreversible aggregates [2] and (b) adapting newly folded proteins to their environment, reducing possible genetic variations between phenotypes [3]. HSPs promote the elimination of denatured proteins via degradation by the proteasome and chaperone-mediated autophagy [4]. These facts are of vital importance in Parkinson’s disease (PD) and other neurodegenerative diseases, in which alteration of protein aggregates can lead to non-functional structures that tend to accumulate. In this review we discuss the possible role of HSP27 as a therapeutic target to avoid the progression of PD
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