====== Neurodegenerative disease pathogenesis ======

The pathogenesis of neuro[[degenerative disease]]s involves complex and interconnected mechanisms that lead to the progressive loss of neurons and their function. While each disease has distinct features, several common pathological processes underlie neurodegeneration:

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===== Protein Misfolding and Aggregation =====

   - **Pathological hallmark:** Misfolded proteins aggregate into toxic forms, disrupting cellular function.
   - **Examples:**
     - **Alzheimer’s disease (AD):** Accumulation of beta-amyloid plaques and hyperphosphorylated tau tangles.
     - **Parkinson’s disease (PD):** Aggregation of alpha-synuclein into Lewy bodies.
     - **Huntington’s disease (HD):** Polyglutamine expansions in the huntingtin protein.
   - **Mechanism:** [[Misfolded proteins]] evade the ubiquitin-proteasome system and [[autophagy]], leading to toxic accumulation and [[neuronal death]].

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### **2. Oxidative Stress**
   - **Definition:** Imbalance between reactive oxygen species (ROS) production and antioxidant defenses.
   - **Impact:** ROS damage proteins, lipids, and DNA, contributing to cellular dysfunction and apoptosis.
   - **Link to diseases:**
     - Mitochondrial dysfunction is a major source of ROS in PD and AD.
     - Impaired oxidative stress responses exacerbate neuronal vulnerability.

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### **3. Mitochondrial Dysfunction**
   - **Role of mitochondria:** Provide energy (ATP) and regulate cellular metabolism.
   - **Dysfunction mechanisms:**
     - Impaired oxidative phosphorylation reduces energy supply.
     - Release of cytochrome c triggers apoptotic pathways.
     - Mitochondrial DNA mutations increase susceptibility.
   - **Implications:** Energy failure and increased oxidative stress contribute to neuronal death.

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### **4. Neuroinflammation**
   - **Key players:**
     - **Microglia:** Overactivated microglia release pro-inflammatory cytokines (e.g., IL-1β, TNF-α) and ROS.
     - **Astrocytes:** Reactive astrocytes exacerbate neurotoxic environments.
   - **Impact:**
     - Chronic inflammation damages neurons and impairs repair mechanisms.
     - Seen in multiple sclerosis, AD, PD, and amyotrophic lateral sclerosis (ALS).

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### **5. Excitotoxicity**
   - **Definition:** Excessive activation of glutamate receptors (e.g., NMDA and AMPA receptors) causes neuronal injury.
   - **Mechanism:**
     - Overactivation leads to calcium influx, triggering cascades of enzymatic reactions.
     - Results in oxidative stress, mitochondrial dysfunction, and cell death.
   - **Diseases:**
     - Prominent in ALS, AD, and ischemic brain injury.

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### **6. Impaired Autophagy and Lysosomal Function**
   - **Autophagy:** Cellular process to degrade and recycle damaged organelles and proteins.
   - **Lysosomal dysfunction:** Impairs degradation of aggregated proteins.
   - **Disease links:**
     - Lysosomal storage disorders contribute to neurodegenerative processes.
     - In PD, mutations in lysosomal enzymes (e.g., GBA1) increase alpha-synuclein aggregation.

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### **7. Genetic and Epigenetic Contributions**
   - **Inherited mutations:**
     - AD: Mutations in **APP**, **PSEN1**, **PSEN2**.
     - PD: Mutations in **LRRK2**, **PINK1**, **SNCA**.
     - ALS: Mutations in **C9orf72**, **SOD1**.
   - **Epigenetics:** DNA methylation, histone modification, and non-coding RNAs influence gene expression and susceptibility.

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### **8. Synaptic Dysfunction**
   - Early loss of synaptic function often precedes neuronal death.
   - Mechanisms:
     - Toxic protein aggregates impair synaptic signaling.
     - Disruption of neurotransmitter release and receptor activity.
   - Diseases:
     - Synaptic dysfunction is a primary feature in AD and HD.

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### **9. Blood-Brain Barrier (BBB) Breakdown**
   - **Role of BBB:** Maintains brain homeostasis and protects against toxins.
   - **Dysfunction:**
     - BBB breakdown allows harmful molecules and immune cells to enter the brain.
     - Exacerbates neuroinflammation and neuronal damage.
   - Seen in AD, MS, and other neurodegenerative diseases.

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### **10. Cellular Senescence**
   - **Definition:** Age-related loss of cellular division and function.
   - **Role in neurodegeneration:**
     - Senescent glial cells secrete pro-inflammatory factors.
     - Accumulation of senescent neurons disrupts brain function.

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### **Interplay of Mechanisms**
These pathways are interconnected and amplify one another:
   - For example, mitochondrial dysfunction exacerbates oxidative stress, which in turn triggers protein aggregation and neuroinflammation.
   - The vicious cycle accelerates neuronal loss and disease progression.

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### **Implications for Therapy**
Understanding these mechanisms guides therapeutic approaches:
   - **Protein clearance:** Targeting aggregation (e.g., monoclonal antibodies in AD).
   - **Antioxidants:** Counteracting oxidative stress (e.g., edaravone in ALS).
   - **Neuroprotective strategies:** Modulating neuroinflammation and excitotoxicity.
   - **Gene therapy:** Correcting genetic defects.
   - **Mitochondrial support:** Enhancing energy production and reducing ROS.

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Accumulation of [[oxidative stress]] is highly intertwined with the aging process and contributes to aging-related diseases, such as [[neurodegenerative disease]]s. Deciphering the molecular machinery that regulates oxidative stress is fundamental to further uncovering the [[pathogenesis]] of these [[disease]]s. [[chaperone-mediated autophagy]] (CMA), a highly selective [[lysosome]]-dependent degradation process, has been proven to be an important maintainer of cellular [[homeostasis]] through multiple mechanisms, one of which is the attenuation of [[oxidative stress]]. However, the specific mechanisms underlying this antioxidative action of CMA are not fully understood. In a study, Zhu et al. found that [[chaperone-mediated autophagy]] (CMA) directly degrades Kelch-like ECH-associated protein 1 ([[Keap1]]), an adaptor of the [[E3 ubiquitin ligase]] complex that promotes the degradation of nuclear factor erythroid 2-related factor 2 ([[Nrf2]]), which is a master transcriptional regulator in antioxidative response. Activated CMA induced by prolonged [[oxidative stress]] led to an increase in [[Nrf2]] level by effectively degrading [[Keap1]], contributing to Nrf2 nuclear [[translocation]] and the expression of multiple downstream antioxidative genes. Meanwhile, together with a previous study showing that Nrf2 can also transcriptionally regulate [[LAMP2]]A, the rate-limiting factor of the CMA process, we reveal a feed-forward loop between CMA and Nrf2. The study identifies CMA as a previously unrecognized regulator of the [[Keap1]]-[[Nrf2]] pathway and reinforces the antioxidative role of [[chaperone-mediated autophagy]] (CMA)
((Zhu L, He S, Huang L, Ren D, Nie T, Tao K, Xia L, Lu F, Mao Z, Yang Q. Chaperone-mediated autophagy degrades Keap1 and promotes [[Nrf2]]-mediated antioxidative response. Aging Cell. 2022 May 10:e13616. doi: 10.1111/acel.13616. Epub ahead of print. PMID: 35535673.)).