By Gilad Rosenberg, MD, MSc, Executive Medical Director, Therapeutic Area Medical Lead, Neuroscience at Allucent
Understanding the Pathology of Neurodegenerative Disorders
Neurodegenerative disorders encompass a range of diseases characterized by the gradual functional decline and eventual death of brain neurons – the fundamental cells of the nervous system that receive, process and transmit signals. Neurodegenerative disorders, which include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic Lateral Sclerosis (ALS) and many other conditions, lead to severe motor, sensory, cognitive, and psychiatric impairments, with immense suffering to patients and their families and significant burden to society.
The inability of neurons to regenerate makes them particularly susceptible to long-term damage and dysfunction. Below, a number of common features of neurodegenerative disorders pathology will be reviewed: protein aggregation, impaired synaptic networking, cytoskeletal issues, impaired energy metabolism, genomic and transcriptomic instability, chronic inflammation, and, ultimately, neuronal death. These processes are interconnected; the understanding of these pathological interactions provides insights for the development of therapeutic agents for neurodegenerative disorders.
Pathological Protein Aggregation
Likely the most central feature of many neurodegenerative disorders is the buildup of misfolded proteins that aggregate and disrupt multiple cellular processes. These protein aggregates often (though not always) correlate with disease severity and/or progression. Specific proteins such as amyloid-beta (Aβ) in AD, alpha-synuclein in PD, and huntingtin in HD undergo structural changes because of genetic mutations and/or environmental factors that enhance their propensity to misfold.
Maintaining protein homeostasis (i.e., the regulated production and clearance of cellular proteins) is critical for normal cellular function. The balance between protein synthesis, folding, and degradation is managed by such systems as the ubiquitin-proteasome system and the autophagy-lysosome pathway. In diseases like AD and PD, the accumulation of misfolded proteins overwhelms these systems, leading to even further intracellular accumulation of misfolded proteins, which is toxic to the cell. Therapeutic strategies that enhance cellular protein clearance are being explored to reduce disease progression. For example, a recent clinical study employed rapamycin – an immunomodulator and an enhancer of autophagy – in the treatment of ALS; however, this study’s results did not clearly support the effects of this drug on ALS progression.
While mature aggregates were initially thought to drive toxicity, emerging evidence indicates that smaller misfolded forms, termed “oligomers”, are also key disruptors of cellular function. Although the precise mechanisms underlying their toxicity require further study, a therapeutic approach that is being vigorously researched aims at removing these oligomers, e.g., through the development of monoclonal antibodies against them. Such efforts were recently crowned with initial success with the approval by the US FDA of several Aβ oligomer-clearing monoclonal antibodies for the treatment of early AD. In neurodegenerative disorders, with known genetic causes, like HD, clinical trials are underway with agents aimed to silence the expression of mutated disease-causing genes.
The propagation of the misfolded proteins to adjacent neurons (cell-to-cell transmission) explains some of the progressive nature of neurodegenerative disorders and offers an opportunity to slow the progression of these disorders by disrupting such transmission. Cell-to-cell transmission is suspected as a main spreading mechanism for alpha-synuclein in PD and other alpha-synuclein-related neurodegenerative disorders, and the reduction of inter-cellular spread by means of antibodies or small molecules that block the recipient cell’s surface receptors for alpha-synuclein aggregates is in pre-clinical testing (of note, more than one mechanism for inter-cellular spread may be involved in a given neurodegenerative disorders).
Synaptic and Neuronal Network Dysfunction
The neuronal dysfunction described above results in the disruption of synaptic communication and in impaired neuronal networking, which are early signs of neurodegeneration detectable even prior to significant neuronal death. Neurotransmission deficits arise from such problems as intracellular calcium excess, mitochondrial dysfunction, cytoskeletal disruptions (discussed below) and glutamate-induced excitotoxicity. For example, in ALS, hyperactivity of motor neurons, possibly due to excessive glutamatergic stimulation, results in increased intracellular calcium levels, which contributes to cellular degeneration. Alternatively, aggregates of proteins such as alpha-synuclein in PD and Aβ in AD are found at synapses, where they disrupt neurotransmitter release and receptor function. Although treatments like L-DOPA in PD and glutamate blockers in ALS provide some symptomatic relief through the modulation of synaptic transmission, they do not address the root cause of neurodegenerative disorders’ synaptic dysfunction, stressing the need for finding truly disease-modifying agents.
Cytoskeletal Abnormalities
The cytoskeleton is vital for maintaining neuronal structure, facilitating intracellular transport along neuronal extensions (axon and dendrites), and supporting effective synaptic activity. In neurodegenerative disorders, cytoskeletal disruptions result in impaired axonal transport and destabilization of neuronal internal architecture. For example, in AD, hyperphosphorylation of tau protein destabilizes microtubules (essential cytoskeleton-building proteins), and in ALS aggregated neurofilaments lead to axonal blockage. These changes can initiate a ‘dying-back’ process, wherein axonal degeneration precedes the neuron’s cell body degeneration. Cytoskeletal biomarkers, e.g., serum and cerebrospinal fluid neurofilament light chain, reflect both axonal damage progression and the clinical course of neurodegenerative disorders.
Altered Energy Homeostasis
Neurons are among the most energy-demanding cells in the body, relying heavily on mitochondria for ATP production. Mitochondrial dysfunction is a recurring feature of neurodegenerative disorders, where mitochondrial dynamics are disrupted by accumulating proteins such as alpha-synuclein and related oligomers. Mitochondrial dysfunction leads to energy shortage, oxidative stress, and impaired calcium regulation. Moreover, mutations in mitochondrial quality control genes (e.g., the Parkin gene in PD) further exacerbate the situation by hindering the elimination of damaged mitochondria through a cellular process known as “mitophagy”. Reduced ATP availability compromises energy-intensive processes like synaptic signaling and protein degradation, creating a vicious cycle: pathological protein aggregation leads to mitochondrial dysfunction which promotes further protein aggregation. While imaging techniques like FDG-PET can identify metabolic impairments in affected brain regions, restoring intracellular energy balance therapeutically remains a major challenge in neurodegenerative disorders.
DNA and RNA Defects
The stability and functionality of DNA and RNA are crucial for neuronal health, yet both are frequently disrupted in neurodegenerative disorders. Due to their high metabolic activity and very limited repair capability, neurons are particularly vulnerable to DNA damage secondary to oxidative stress. DNA damage, if unrepaired, can accumulate over time and trigger cell death pathways. Moreover, mutations in genes involved in DNA repair are associated with increased vulnerability to certain neurodegenerative disorders.
RNA metabolism is similarly affected. In diseases such as ALS and frontotemporal dementia the aggregation of key proteins like TDP-43 disrupts normal RNA splicing, transport, and stability. Stress granules formed during periods of cellular strain further contribute to this dysfunction by sequestering essential RNA-binding proteins. Lastly, toxic RNA species, e.g., those derived from repeat nucleotide expansions in the C9orf72 gene (a common mutation found in ALS and frontotemporal dementia), also contribute to neurodegenerative disorders’ pathology, indicating again that in some neurodegenerative disorders therapy may require the silencing of mutated genes by means of, e.g., antisense oligonucleotides.
Inflammation
Inflammation plays a complex role in neurodegenerative disorders, being both protective and harmful. Acute inflammatory response can aid in clearing debris and promoting repair, but chronic inflammation often drives neurodegeneration. Activated microglia, the brain’s resident immune cells, respond to pathological protein aggregates by releasing pro-inflammatory cytokines and reactive oxygen species, which can harm neurons. Astrocytes – neuron-supporting cells that regulate synaptic activity and glutamate production – become similarly reactive in neurodegenerative disorders and further exacerbate the inflammatory responses. Variations in genes related to the inflammation, e.g., in TREM2 – a protein that promotes clearance of Aβ aggregate, influence how such cells respond to protein aggregation, affecting disease progression and severity. Therapies aimed at modulating inflammation in neurodegenerative disorders must balance the reduction in inflammation’s harmful effects against the loss of its favourable aspects. Many clinical trials of immunomodulatory agents in neurodegenerative disorders have been performed to-date, all without clinical benefit, raising doubts about the centrality of brain inflammation in these disorders.
Neuronal Cell Death
The final outcome of neurodegenerative pathologies is the irreversible loss of neurons. Neuronal death arises through multiple mechanisms, all triggered by the above-mentioned cellular stressors. Developing effective neuroprotective therapies requires an integrated approach that targets the interplay of these versatile destructive pathways rather than focusing on a single pathological process. This is a difficult target to meet; indeed, multiple clinical trials with a variety of ostensibly neuroprotective agents have been performed in neurodegenerative disorders, but so far yielded disappointing results.
Conclusion
The main features of neurodegeneration – protein aggregation, synaptic dysfunction, cytoskeletal abnormalities, energy crisis, DNA/RNA defects, inflammation and neuronal loss – represent an interconnected network of damage. Understanding this network offers valuable insights into the evolution of neurodegenerative disorders, providing clues for the development of innovative therapies aimed at halting, or at least slowing down, neurodegenerative disorders’ progression. Moreover, understanding these processes will aid in the development of biomarkers that can reflect both disease progression and the effect of disease-modifying interventions in clinical research as well as in routine practice.
Allucents Center of Expertise (ACE) for Neuroscience and Psychiatry has a dedicated team of cross-functional experts who can help you choose therapeutic targets in neurodegenerative disorders, design proof-of-concept and confirmatory clinical trials and interact with relevant regulatory authorities. Allucent brings new therapies to light by solving the distinct challenges of small and mid-sized biotech companies. We’re a global provider of comprehensive drug development solutions, including consulting, clinical operations, biometrics, and clinical pharmacology across a variety of therapeutic areas. Our individualized partnership approach provides experience-driven insights and expertise to assist clients in successfully navigating the complexities of delivering novel treatments to patients. For more details about how the A-Team can support your drug development programs, visit us today
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