Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms
Tauopathies are a diverse group of diseases featuring progressive dying-back neurodegeneration of specific neuronal populations in association with accumulation of abnormal forms of the microtubule-associated protein tau. It is well-established that the clinical symptoms characteristic of tauopathie...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2017-10-01
|
| Series: | Frontiers in Neuroscience |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fnins.2017.00572/full |
| _version_ | 1818963509499658240 |
|---|---|
| author | Andrew Kneynsberg Andrew Kneynsberg Benjamin Combs Kyle Christensen Kyle Christensen Gerardo Morfini Nicholas M. Kanaan Nicholas M. Kanaan Nicholas M. Kanaan |
| author_facet | Andrew Kneynsberg Andrew Kneynsberg Benjamin Combs Kyle Christensen Kyle Christensen Gerardo Morfini Nicholas M. Kanaan Nicholas M. Kanaan Nicholas M. Kanaan |
| author_sort | Andrew Kneynsberg |
| collection | DOAJ |
| description | Tauopathies are a diverse group of diseases featuring progressive dying-back neurodegeneration of specific neuronal populations in association with accumulation of abnormal forms of the microtubule-associated protein tau. It is well-established that the clinical symptoms characteristic of tauopathies correlate with deficits in synaptic function and neuritic connectivity early in the course of disease, but mechanisms underlying these critical pathogenic events are not fully understood. Biochemical in vitro evidence fueled the widespread notion that microtubule stabilization represents tau's primary biological role and that the marked atrophy of neurites observed in tauopathies results from loss of microtubule stability. However, this notion contrasts with the mild phenotype associated with tau deletion. Instead, an analysis of cellular hallmarks common to different tauopathies, including aberrant patterns of protein phosphorylation and early degeneration of axons, suggests that alterations in kinase-based signaling pathways and deficits in axonal transport (AT) associated with such alterations contribute to the loss of neuronal connectivity triggered by pathogenic forms of tau. Here, we review a body of literature providing evidence that axonal pathology represents an early and common pathogenic event among human tauopathies. Observations of axonal degeneration in animal models of specific tauopathies are discussed and similarities to human disease highlighted. Finally, we discuss potential mechanistic pathways other than microtubule destabilization by which disease-related forms of tau may promote axonopathy. |
| first_indexed | 2024-12-20T12:46:21Z |
| format | Article |
| id | doaj.art-391733b04f894983bb7c900b47fd37ae |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-20T12:46:21Z |
| publishDate | 2017-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-391733b04f894983bb7c900b47fd37ae2022-12-21T19:40:18ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2017-10-011110.3389/fnins.2017.00572284198Axonal Degeneration in Tauopathies: Disease Relevance and Underlying MechanismsAndrew Kneynsberg0Andrew Kneynsberg1Benjamin Combs2Kyle Christensen3Kyle Christensen4Gerardo Morfini5Nicholas M. Kanaan6Nicholas M. Kanaan7Nicholas M. Kanaan8Neuroscience Program, Michigan State University, East Lansing, MI, United StatesDepartment of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United StatesDepartment of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United StatesNeuroscience Program, Michigan State University, East Lansing, MI, United StatesDepartment of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United StatesDepartment of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, United StatesNeuroscience Program, Michigan State University, East Lansing, MI, United StatesDepartment of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United StatesHauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, MI, United StatesTauopathies are a diverse group of diseases featuring progressive dying-back neurodegeneration of specific neuronal populations in association with accumulation of abnormal forms of the microtubule-associated protein tau. It is well-established that the clinical symptoms characteristic of tauopathies correlate with deficits in synaptic function and neuritic connectivity early in the course of disease, but mechanisms underlying these critical pathogenic events are not fully understood. Biochemical in vitro evidence fueled the widespread notion that microtubule stabilization represents tau's primary biological role and that the marked atrophy of neurites observed in tauopathies results from loss of microtubule stability. However, this notion contrasts with the mild phenotype associated with tau deletion. Instead, an analysis of cellular hallmarks common to different tauopathies, including aberrant patterns of protein phosphorylation and early degeneration of axons, suggests that alterations in kinase-based signaling pathways and deficits in axonal transport (AT) associated with such alterations contribute to the loss of neuronal connectivity triggered by pathogenic forms of tau. Here, we review a body of literature providing evidence that axonal pathology represents an early and common pathogenic event among human tauopathies. Observations of axonal degeneration in animal models of specific tauopathies are discussed and similarities to human disease highlighted. Finally, we discuss potential mechanistic pathways other than microtubule destabilization by which disease-related forms of tau may promote axonopathy.http://journal.frontiersin.org/article/10.3389/fnins.2017.00572/fullaxonal transportAlzheimer's disease (AD)chronic traumatic encephalopathy (CTE)pick's diseaseprogressive supranuclear palsycorticobasal degeneration |
| spellingShingle | Andrew Kneynsberg Andrew Kneynsberg Benjamin Combs Kyle Christensen Kyle Christensen Gerardo Morfini Nicholas M. Kanaan Nicholas M. Kanaan Nicholas M. Kanaan Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms Frontiers in Neuroscience axonal transport Alzheimer's disease (AD) chronic traumatic encephalopathy (CTE) pick's disease progressive supranuclear palsy corticobasal degeneration |
| title | Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms |
| title_full | Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms |
| title_fullStr | Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms |
| title_full_unstemmed | Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms |
| title_short | Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms |
| title_sort | axonal degeneration in tauopathies disease relevance and underlying mechanisms |
| topic | axonal transport Alzheimer's disease (AD) chronic traumatic encephalopathy (CTE) pick's disease progressive supranuclear palsy corticobasal degeneration |
| url | http://journal.frontiersin.org/article/10.3389/fnins.2017.00572/full |
| work_keys_str_mv | AT andrewkneynsberg axonaldegenerationintauopathiesdiseaserelevanceandunderlyingmechanisms AT andrewkneynsberg axonaldegenerationintauopathiesdiseaserelevanceandunderlyingmechanisms AT benjamincombs axonaldegenerationintauopathiesdiseaserelevanceandunderlyingmechanisms AT kylechristensen axonaldegenerationintauopathiesdiseaserelevanceandunderlyingmechanisms AT kylechristensen axonaldegenerationintauopathiesdiseaserelevanceandunderlyingmechanisms AT gerardomorfini axonaldegenerationintauopathiesdiseaserelevanceandunderlyingmechanisms AT nicholasmkanaan axonaldegenerationintauopathiesdiseaserelevanceandunderlyingmechanisms AT nicholasmkanaan axonaldegenerationintauopathiesdiseaserelevanceandunderlyingmechanisms AT nicholasmkanaan axonaldegenerationintauopathiesdiseaserelevanceandunderlyingmechanisms |