In a recent study published in Cell, researchers presented eight hallmarks of neurodegenerative diseases (NDDs), their in vivo biomarkers, and interactions to help categorize NDDs and specify patients within a specific NDD.
Study: Hallmarks of neurodegenerative diseases. Image Credit: ART-ur/Shutterstock
Despite being linked to rare genetic forms, all eight NDD hallmarks (cellular/molecular processes) also contribute to sporadic NDDs. In addition, they contribute to neuronal loss in preclinical (animal) models and NDD patients, manifesting as an altered molecular (hallmark) biomarker.
An NDD patient could have defects in multiple NDD hallmarks. However, the primary NDD hallmark depends on the NDD insult and the neuronal susceptibility and resilience, i.e., one's ability to handle insults in the affected brain region.
NDDs affects millions globally, causing irreversible loss of neurons in the central and peripheral nervous system (CNS/PNS). It eventually impairs or breaks down the core cognitive, sensory, memory, and motor functions in the affected patients.
The following are the eight hallmarks of NDDs:
Pathological protein aggregation
There is adequate data on the contribution of protein aggregation to the neurodegenerative process in proteinopathic NDDs, examples of which include Alzheimer's disease (AD), Parkinson's disease (PD), and prion disease (PrD). For many of these NDDs, protein aggregates have been identified in brain regions. However, this phenomenon could also contribute to disease progression in combination with other hallmarks of NDDs.
In non-proteinopathic diseases, e.g., traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), stroke, spinal cord injury (SCI), and multiple sclerosis (MS), the primary neuronal insult is unrelated to protein aggregation. However, several such NDDs display protein aggregation as a secondary effect, contributing to a chronic aggravating phase (e.g., tau in TBI).
A causal link between these disease-causing mutations and amplified aggregation of the encoded protein is a common feature among different NDDs, supporting a toxic gain-of-function (GOF) mechanism. Examples include several genes encoding amyloid precursor protein (APP) and tau in AD and α-synuclein in PD. Note that some NDD mutations do not lead to aggregation of the encoded protein but instead increase aggregation of key NDD proteins, e.g., Presenilin 1 and 2 (PSEN1, PSEN2). Moreover, protein aggregates do not always correlate perfectly with the disease process. Together, these findings suggest that alternative mechanisms for neurotoxicity exist and other unique molecular events (distinct from aggregating proteins) also contribute to the NDDs.
Amyloid-beta (Aβ) positron emission tomography (PET) could be used to monitor amyloid deposition during AD. This assay detects the onset of Aβ aggregation much before the clinical onset of the disease.
Synaptic and neuronal network dysfunction
Neuronal network function requires precise synaptic function, which, in turn, requires a tight regulation of mitochondrial function and energy supply to maintain calcium homeostasis and ionic balance. Elimination and replenishment of constituents for a proper synaptic function are also energy-dependent. Furthermore, astrocytes and microglia are important in synapse stabilization and elimination.
Studies have implicated glutamate-mediated excitotoxicity with amyotrophic lateral sclerosis (ALS) etiology and neurodegenerative processes in AD, MS, SCI, and TBI. Additionally, several genes linked to proper synaptic function get mutated in certain NDDs, for instance, synuclein alpha (SNCA) in PD.
Therapeutic interventions based on the modulation of neurotransmission improve NDD symptoms. For instance, replacing the lost dopamine signal using the amino acid l-3,4-dihydroxyphenylalanine (L-DOPA) temporally restore motor symptoms in early to moderate PD.
Several diagnostic assays indicate early synaptic network dysfunction in NDDs. Examples include functional magnetic resonance imaging (fMRI), which assesses neuronal network connectivity, and fluorodeoxyglucose-PET (FDG-PET), which reveals decreased glucose metabolism in AD.
Aberrant proteostasis
Two cellular pathways, the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP), help maintain protein homeostasis. While the former mainly degrades marked proteins, the latter eliminates protein aggregates and defective organelles.
Starvation- or stress-induced low energy or low availability of specific amino acids triggers these pathways, highlighting their interconnection with other NDD hallmarks.
In addition, aggregation of proteins associated with sporadic NDDs, such as tau, impairs UPS function, suggesting a wider association with more common forms of NDD. Gaucher disease and Niemann-Pick’s disease type C1 (NPC), linked to lysosomal defects, give rise to altered cholesterol or lipid homeostasis, respectively. Also, aggregating proteins of lysosomal storage disorders (LSDs) parallel the symptoms of certain NDDs (e.g., tau in NPC).
Cytoskeletal abnormalities
The three neuronal cytoskeletal structures, tubulin-based microtubules, neurofilaments, and actin-based microfilaments, facilitate the building, maintenance, and transformation of neurons and transport of mitochondria along their extended lengths, thereby supporting energy homeostasis.
The mutations in the neuronal intermediate light filament (NEFL) gene in Charcot-Marie-Tooth disease (CMT) encode the microtubule-binding protein tau providing direct evidence for the importance of altered cytoskeletal function in NDDs. Moreover, many NDDs contain aggregates of tau, actin, or neurofilament.
Accordingly, neurofilament concentrations in biofluids have emerged as promising clinical biomarkers for multiple neurological disorders, including stroke and dementia. These assays quantify neurofilaments at femtomolar concentrations in peripheral blood, further underscoring that cytoskeletal defects are a common hallmark of NDDs. Notably, cytoskeletal disruptions also interact with other NDD hallmarks, particularly synaptic dysfunction and protein aggregation.
Altered energy homeostasis
Neurons are the most energy-demanding cells of the human body. Thus, defects in energy metabolism have been implicated in many NDDs.
Note adenosine triphosphate (ATP), the key molecule of brain energy metabolism, is synthesized in mitochondria by oxidative phosphorylation fueled by glucose/lactate metabolism. Thus, mitochondrial dysfunction also occurs in several NDDs, including AD and ALS, as part of the pathogenic process. Also, altered energy homeostasis is tightly linked to neuronal cell death.
DNA and RNA defects
Several NDDs, mostly recessive ataxias, also originate from inherited defects in the ability to resolve deoxyribonucleic acid (DNA) single-strand breaks (SSBs), frequent products of reactive oxygen species (ROS) attack of DNA. Studies have implicated rare dominant mutations in a juvenile-onset form of ALS with neuronal cell death. Likewise, studies have suggested RNA defects as a driving mechanism in NDDs, including multisystem proteinopathy (MSP), caused by mutations in two nuclear genes.
Inflammation
Neuroinflammation, including astrogliosis and microgliosis, are two other pathological hallmarks of NDDs, including AD, PD, and stroke. Besides, neuroinflammation is implicated in neurodegeneration in diseases such as MS.
Neuronal cell death
Indeed, NDD hallmarks converge on neuronal death, as the final stage of NDDs is the loss of the neuronal cell population leading to impaired functionality. There are several causes of neuronal death. For instance, excitotoxicity and energy depletion; in addition to the cell-autonomous death pathways, non-cell autonomous processes contribute to neuronal loss.
For example, activated microglia phagocytose apoptotic cells to limit neuroinflammation. Intriguingly, apoptotic neurons flag an eat-me signal by exposing phosphatidylserine (PS) on their surface.
Neurons are inherently vulnerable to cell death in NDD. First, because they are unable to replicate and replenish themselves, and second, they have high energy requirements, mainly due to the need to support synaptic function. Finally, other NDD hallmarks act together to override their intrinsic resilience to internal and external insults.
Conclusions
The proposed holistic study framework categorized different NDDs based on their primary hallmarks, identified with the help of improved biomarkers. In addition, they summed up the genetic and biochemical processes and pathways that contribute to NDDs, uncovering the overlapping biological processes between NDDs and the interconnectedness of their eight hallmarks.
A remarkable example of a high degree of interconnectedness between different NDD hallmarks is the close link between synaptic dysfunction and energy homeostasis, leading to neuronal death.
Another significant finding of this study was that within a given NDD, genetic and environmental factors might shift the relative contribution of the different NDD hallmarks. For instance, among AD patients, one subset might have a protein aggregation component, while the other might have a strong synaptic component. Thus, they would benefit differently from different components of the multi-targeted therapy.
Indeed, this work lays the foundation for customized therapies to treat NDDs. However, it also raises the need for multimodal biomarker panels that simultaneously target multiple systems during the therapy as they appear crucial in identifying NDD patients in the pre-symptomatic disease stages.
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