New Inroads Into Our Understanding of the Tauopathies, Alzheimer's Disease, and the Contribution of Altered Protein Conformation to Human Neurological Disease

Recent Advances in Our Molecular and Mechanistic Understanding of Misfolded Cellular Proteins in Alzheimer’s Disease (AD) and Prion Disease (PrD)

“…The identification and appreciation of these complex molecular processes remains both enigmatic and fascinating for a number of reasons. These include: ( i ) the implication that both of these progressive age-related disorders are, in a large part, based on the abnormal folding of endogenous natural protein structures into unusual pathogenic isoforms that, over time, can stimulate the atypical folding of other natural brain-enriched proteins; ( ii ) that this induction of misfolded pathogenic proteins from normal proteins may be partly based on their underlying primary amino acid sequence, thus defining a set of biological and biochemical parameters which favor such a pathological conformational transition in certain types of brain proteins; ( iii ) that these novel and unique disease processes, notably without the direct involvement of nucleic acids, also provide a mechanistic foundation for ‘seeding’ or disease spreading that may partly occur via leakage of these peptides and/or proteins through normally protective biological barriers or perhaps via intra- or inter-cellular signaling via exosomes and/or through extracellular micro-vesicular transport [ 39 , 40 ]; ( iv ) the implication that the rate of abnormal protein folding may be augmented and/or amplified by other neurotoxic pathological factors, environmental toxins and/or processes that alter the native polypeptide conformation to ultimately promote protein misfolding; ( v ) the general inference that these pathological processes are extraordinarily similar to those involving the generation, propagation, diffusion and spreading of prions in multiple mammalian neurological disorders [ 28 , 29 ]; and ( vi ) the intriguing possibility that specific abnormally folded brain proteins have pivotal roles in the initiation, propagation, and perhaps the ‘seeding’ and/or ‘horizontal transmission’ within the entire spectrum of misfolded MAPT-, α-synuclein- and/or Aβ peptide-linked neurodegenerative diseases observed to occur in multiple susceptible mammalian species [ 12 , 34 , 36 , 39 ].…”

“…Major medical, scientific and technological challenges are to conceive and implement standardized analytical approaches, techniques and protocols to accurately categorize neurological disorders based on the pathological molecular structure of the underlying abnormal tau protein assemblies. This will achieve an increased accuracy in the diagnosis, prognosis and effective therapies for the clinical management of the wide spectrum of neurological diseases involving misfolded MAPT, Aβ peptides and the related neuronal-enriched fibrillar proteins, and their closely related potential for self-aggregation, as well as the seeding, progression and propagation of neuropathological events [ 12 , 35 , 36 , 39 ].…”