Neurodegeneration

By Bethany Veo, PhD

By Bethany Veo, PhD

The neurodegenerative disorder, Alzheimer's disease, is responsible for 60 to 80% of all dementia cases.¹   Neurodegeneration occurs in response to the accumulation of amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau.

Alzheimer’s Disease (AD) is a neurodegenerative disorder that is characterized by an abundance of the beta-amyloid peptide in the brain.  When AD was first discovered, it was determined that beta-amyloid was produced as a result of the proteolysis of the amyloid precursor protein (APP).  Aside from its role in AD, the single-pass transmembrane APP has a high expression level in the brain and tends to concentrate at the synapses of neurons.  Because of this localization, it has been suggested that APP plays a role in synapse formation and potentially plasticity.  However, the

Niemann-Pick type C1 (NPC1) mediates low-density cholesterol transport from late endosomes and lysosomes to other areas of the cell via receptor mediation endocytosis.  Although cholesterol moves freely inside the cell, it cannot independently export out of the lysosome, which is where NPC1 steps in.

Microtubules are a main component of the cytoskeleton and play essential roles in a variety of cellular processes. These highly dynamic tubular structures are assembled from alpha- and beta-tubulin dimers to form a complex structural network of microtubules throughout the cytoplasm. This network provides a substrate for intracellular trafficking of vesicles, organelles, and other cargo and can also facilitate cell migration. Additionally, during cell division, microtubules make up the mitotic spindle and provide the mechanical force for chromosome segregation.

The tau protein is a microtubule associated protein found mostly in neuronal cells where it regulates the stability of axonal microtubules as well as kinesin-dependent transport. Tau is relevant in the study of various neurological disorders as abnormal post translational modifications can alter its structure and lead to protein aggregates. Tau is present on microtubules in neuronal cells and is also associated with the plasma membrane.

Matrix metalloproteinases (MMPs) are responsible for the degradation of extracellular matrix proteins. MMPs are essential for tissue remodeling during normal processes such as embryonic development as well as pathological conditions such as arthritis and tumor metastasis. MMP3, a member of the stromelysin family, has broad specificity for proteins such as collagens, fibronectin, proteoglycans, and elastin making it an important player in extracellular matrix remodeling. These activities are especially important during tumorigenesis by enhancing epithelial to mesenchymal transition.

PTEN-induced putative kinase 1 (PINK1) is a serine/threonine kinase with important functions in mitochondrial quality control. Together with the Parkin protein, PINK1 is able to regulate the selective degradation of damaged mitochondria through autophagy. Normally PINK1 is imported into the mitochondria where it is targeted for proteolytic cleavage. This cleavage event results in unstable products and is the reason PINK1 is difficult to detect in healthy mitochondria.

Heat shock cognate 71 kDa protein (Hsc70), also known as HSPA8, is a member of the heat shock protein 70 family (Hsp70). Unlike Hsp70, it is a constitutively expressed chaperone protein and is involved in diverse cellular processes including protein folding and protein degradation. Hsc70 consists of two domains: the nucleotide binding domain (NBD) and the substrate binding domain (SBD). Hsc70, with the help of accessory proteins, exerts its chaperone activity by binding to short hydrophobic stretches of nascent or unfolded polypeptides through the SBD in an ATP-dependent manner.