Accumulation Of Toxic Aggregates Research Articles

Lysosomal Channels as New Molecular Targets in the Pharmacological Therapy of Neurodegenerative Diseases via Autophagy Regulation.

Besides controlling several organellar functions, lysosomal channels also guide the catabolic "self-eating" process named autophagy, which is mainly involved in protein and organelle quality control. Neuronal cells are particularly sensitive to the rate of autophagic flux either under physiological conditions or during the degenerative process. Accordingly, neurodegeneration occurring in Parkinson's (PD), Alzheimer's (AD), and Huntington's Diseases (HD), and Amyotrophic Lateral Sclerosis (ALS) as well as Lysosomal Storage Diseases (LSD) is partially due to defective autophagy and accumulation of toxic aggregates. In this regard, dysfunction of lysosomal ionic homeostasis has been identified as a putative cause of aberrant autophagy. From a therapeutic perspective, Transient Receptor Potential Channel Mucolipin 1 (TRPML1) and Two-Pore Channel isoform 2 (TPC2), regulating lysosomal homeostasis, are now considered promising druggable targets in neurodegenerative diseases. Compelling evidence suggests that pharmacological modulation of TRPML1 and TPC2 may rescue the pathological phenotype associated with autophagy dysfunction in AD, PD, HD, ALS, and LSD. Although pharmacological repurposing has identified several already used drugs with the ability to modulate TPC2, and several tools are already available for the modulation of TRPML1, many efforts are necessary to design and test new entities with much higher specificity in order to reduce dysfunctional autophagy during neurodegeneration.

Extracellular vesicles: the key to unlocking mechanisms of age-related vascular disease?

Aging is associated with the development of two ubiquitous, detrimental pathologies, vascular calcification and amyloidosis. These pathologies are characterized by the accumulation of toxic aggregates in the vessel extracellular matrix (ECM) in the form of crystalline calcium and phosphate mineral or insoluble protein fibrils, respectively. These aggregates impact ECM integrity, drive vascular stiffening, and can also cause cell death and phenotypic change in the cells that interact with them. The deposition of both calcification and amyloid requires a nucleus that can mediate the mineralization of calcium and phosphate, or amyloid aggregation from precursor proteins or peptides. Emerging evidence suggests that changes in the composition of the ECM associated with cellular senescence, as well as extracellular vesicle (EV) release, cargo-loading, trapping, and aggregation within the ECM, are common and synergistic mechanisms that regulate the development of these pathologies. Importantly, vascular smooth muscle cells (VSMCs) orchestrate the formation of both pathologies that commonly co-occur in the aging vasculature. Here, we outline the commonalities and differences in what is known about the genesis of calcification and amyloid, and highlight key questions and areas that remain unknown and require further investigation. The complex relationship between senescence, EVs, and the ECM, mediated by VSMCs, which drives the accumulation of HA and amyloid, could be a target for therapeutic intervention.

Vocal changes in a zebra finch model of Parkinson's disease characterized by alpha-synuclein overexpression in the song-dedicated anterior forebrain pathway.

Deterioration in the quality of a person’s voice and speech is an early marker of Parkinson’s disease (PD). In humans, the neural circuit that supports vocal motor control consists of a cortico-basal ganglia-thalamo-cortico loop. The basal ganglia regions, striatum and globus pallidus, in this loop play a role in modulating the acoustic features of vocal behavior such as loudness, pitch, and articulatory rate. In PD, this area is implicated in pathogenesis. In animal models of PD, the accumulation of toxic aggregates containing the neuronal protein alpha-synuclein (αsyn) in the midbrain and striatum result in limb and vocal motor impairments. It has been challenging to study vocal impairments given the lack of well-defined cortico-basal ganglia circuitry for vocalization in rodent models. Furthermore, whether deterioration of voice quality early in PD is a direct result of αsyn-induced neuropathology is not yet known. Here, we take advantage of the well-characterized vocal circuits of the adult male zebra finch songbird to experimentally target a song-dedicated pathway, the anterior forebrain pathway, using an adeno-associated virus expressing the human wild-type αsyn gene, SNCA. We found that overexpression of αsyn in this pathway coincides with higher levels of insoluble, monomeric αsyn compared to control finches. Impairments in song production were also detected along with shorter and poorer quality syllables, which are the most basic unit of song. These vocal changes are similar to the vocal abnormalities observed in individuals with PD.

A cognizance analysis on amyotrophic lateral sclerosis in Middle East countries

ALS, or amyotrophic lateral sclerosis, is a progressive neurodegenerative disease, affects nerve cells in the brain and spinal cord [1]. Ever since, the repeat expansions in the C9ORF72 gene were identified as a major cause of ALS and frontotemporal dementia, researchers have been debating whether the disease is caused by loss of normal protein(s) or accumulation of toxic aggregates [2]. Amyotrophic lateral sclerosis (ALS) epidemiology has rapidly developed in the Middle East, was spread after the gulf war [3]. In 2015, there were 45,810 men and 34,352 women diagnosed with ALS in the developed countries. The projected number ALS is expected to grow from 80,162 in 2015 to 105,693 in 2040, represents an increase of >31%. In Middle East (like, Iran) there is high prevalence in ALS, 112% (Fig-1), due to insignificant awareness on ALS [4]. The recent discovery of pathological TDP-43 in both ALS and FTLD-U confirms a new biochemical class neurodegenerative disease, called TDP-43 proteinopathies [5]. Recently, researchers developed an antibody that reduces the number of TDP-43 protein aggregates in the mice brains with ALS, resulting in significant improvements in their cognitive and motor performance (Fig-2). Preliminary results suggest that injecting TDP-43 antibodies directly into the cerebrospinal fluid could effectively reduce protein aggregates in nerve cells [6]. The current cognizance analysis focus on the mechanism of single-chain (scFv) antibodies against the RNA recognition motif 1 (RRM1) of TDP-43 protein aggregates in the ALS pathology.

Modulating SOD1 Folding Landscapes with Targeted Molecular Binders

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the deterioration of motor neurons that abates essential biological functions and exhibits survival times of 3 - 5 years after diagnosis. One driver of this disease derives from inherited mutations to the protein superoxide dismutase 1 (SOD1), which hinder proper folding and result in the accumulation of toxic aggregates. We identified cyclic peptides that target precise epitopes on SOD1 through an emerging screening platform that furnishes high-affinity binders against regions of a protein independent of secondary or tertiary structure. Binding these epitopes both stabilizes the native state and accelerates folding. In this context, these small peptides function as molecular chaperones and mitigate the impact of deleterious mutations to SOD1. They also display the traditional benefits of small molecules, such as straightforward chemical modifications and long-term stability. Overall, this method provides a route to rationally perturb the energy landscape of any protein through noncovalent binding, making it useful in fundamental studies of protein folding as well as designing therapeutics for misfolding diseases.

Proteostasis and the aging proteome in health and disease.

The maintenance of the proteome is essential to preserve cell functionality and the ability to respond and adapt to the changing environment. This is regulated by the proteostasis network, a dedicated set of molecular components comprised of molecular chaperones and protein clearance mechanisms, regulated by cell stress signaling pathways, that prevents the toxicity associated with protein misfolding and accumulation of toxic aggregates in different subcellular compartments and tissues. The efficiency of the proteostasis network declines with age and this failure in protein homeostasis has been proposed to underlie the basis of common age-related human disorders. The current advances in the understanding of the mechanisms and regulation of proteostasis and of the different types of digressions in this process in aging have turned the attention toward the therapeutic opportunities offered by the restoration of proteostasis in age-associated degenerative diseases. Here, we discuss some of the unresolved questions on proteostasis that need to be addressed to enhance healthspan and to diminish the pathology associated with persistent protein damage.

Are cheetahs on the run from prion-like amyloidosis?

The misfolding and aggregation of proteins is often an accident waiting to happen. Consequently, organisms have developed sophisticated chaperone and quality-control systems to limit abnormal protein interactions and the accumulation of toxic aggregates (1). However, sometimes these systems can be overwhelmed, and diseases, namely protein misfolding diseases, can result. One such disease, amyloid protein A (AA) amyloidosis, is wreaking havoc in the captive cheetah population, complicating efforts to rescue this endangered species from extinction (2, 3). One key to managing this fatal disease in cheetahs is to understand why it is so prevalent. Most cases of AA amyloidosis in mammals appear to occur spontaneously, usually as a result of chronic inflammation or genetic peculiarities that predispose the organism to the deposition of serum amyloid A (SAA) protein in fibrillar deposits called amyloid (Fig. 1). In this issue of PNAS, Zhang et al. (4) report that AA amyloid is excreted in the feces of cheetahs with AA amyloidosis and that this fecal amyloid can in turn promote a similar disease in mice. These results suggest that cheetah AA amyloidosis may not be simply a spontaneous disease, but also a natural prion-like, transmissible protein misfolding disease.