Interplay of endoplasmic reticulum stress and autophagy in neurodegenerative disorders

Abstract

The common underlying feature of most neurodegenerative diseases such as Alzheimer disease (AD), prion diseases, Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) involves accumulation of misfolded proteins leading to initiation of endoplasmic reticulum (ER) stress and stimulation of the unfolded protein response (UPR). Additionally, ER stress more recently has been implicated in the pathogenesis of HIV-associated neurocognitive disorders (HAND). Autophagy plays an essential role in the clearance of aggregated toxic proteins and degradation of the damaged organelles. There is evidence that autophagy ameliorates ER stress by eliminating accumulated misfolded proteins. Both abnormal UPR and impaired autophagy have been implicated as a causative mechanism in the development of various neurodegenerative diseases. This review highlights recent advances in the field on the role of ER stress and autophagy in AD, prion diseases, PD, ALS and HAND with the involvement of key signaling pathways in these processes and implications for future development of therapeutic strategies.

Keywords: ER stress; Parkinson disease; alzheimer disease; amyotrophic lateral sclerosis and HIV-associated neurocognitive disorders; autophagy; neurodegenerative disorders; prion diseases.

Figure 1.

ER stress and UPR pathways in neuronal cells. Pathological accumulation of misfolded proteins and/or depletion of ER calcium store via activation of ITPR and RYR leads to ER stress. Dissociation of HSPA5 from 3 ER stress sensors, EIF2AK3, ERN1 and ATF6, results in phosphorylation of EIF2AK3 and ERN1 and translocation of ATF6 to the Golgi apparatus. Activated EIF2AK3 is a serine/threonine protein kinase that phosphorylates EIF2S1. p-EIF2S1 (phosphorylated EIF2S1) inhibits global protein synthesis but selectively upregulates ATF4, PPP1R15A, DDIT3 and ATF3. PPP1R15A provides a negative feedback by dephosphorylating p-EIF2S1. ERN1 cleaves XBP1 mRNA; the spliced form of XBP1 encodes the XBP1 protein. XBP1 increases the expression of genes encoding ER chaperones, ERAD proteins and lipid synthesis to restore the capacity of protein folding. ATF6 is translocated to the Golgi apparatus where it is cleaved by MBTPS1 and MBTPS2, and cleaved ATF6 stimulates the expression of ER chaperones and ERAD proteins. Apoptosis will ensue if upregulation of ER chaperones and ERAD proteins fails to rescue ER stress.

Figure 2.

The autophagic cascade in neurodegenerative disorders. Stress stimuli associated with neurodegenerative disorders inhibits MTORC1, resulting in activation of the ULK1 complex. The ULK1 complex can also be activated by AMPK. The ULK1 complex initiates vesicle nucleation by translocating BECN1 and PtdIns3K to phagophores. To elongate the membrane from the phagophore assembly site (PAS), The ATG12–ATG5 conjugate regulates the conjugation of PE to MAP1LC3B, resulting in conversion of MAP1LC3B from soluble MAP1LC3B-I into phagophore and autophagosome-associated MAP1LC3B-II. Once the autophagosome is formed, it fuses with a lysosome for degradation of its sequestered cargo.

Figure 3.

The interplay between the UPR and autophagy. EIF2AK3-EIF2S1 signaling induces the expression of various autophagy-related proteins via ATF4 and DDIT3. ERN1 triggers autophagy through activation of AMPK and dissociation of BECN1 from BCL2 via MAPK8-dependent phosphorylation of BCL2. Conversely, XBP1 that acts as the downstream mediator of ERN1 provides negative feedback for autophagy by promoting degradation of FOXO1. Upregulation of DAPK1 induced by cleaved ATF6 phosphorylates BECN1 and leads to dissociation of BECN1 from BCL2, resulting in enhanced autophagic activities.

Figure 4.

ER stress and autophagy in AD. Both mPSEN1 (mutant PSEN1) and Aβ induce calcium-dependent ER stress, resulting in astrogliosis and neuronal injury. Loss of BECN1 not only contributes to neuronal damage but also debilitates the phagocytic function and induces inflammatory responses in microglia. Interestingly, mPSEN1 renders neurons vulnerable to ER stress by suppressing major UPR mediators while MAPT protein enhances its phosphorylation through activation of UPR mediators, especially EIF2AK3. The EIF2AK3-dependent autophagy pathway is crucial for degradation of Aβ, and autophagic activities can be also enhanced by genetic deletion of CSTB/cystatin B or treatment with temsirolimus. However, autophagy mediated by EIF2AK3 signaling also activates GSK3B by removing its inactive form resulting in subsequent phosphorylation and aggregation of MAPT protein. Moreover, ATPase inhibitors for HSPA/DNAJ complexes and HSP90 multi-component complexes facilitate the triage of MAPT toward the ERAD pathway. CLU and TTR are able to bind to aggregated proteins to prevent their aggregation.

Figure 5.

ER stress and autophagy in prion diseases. ER stress induced by disruption of intracellular calcium homeostasis is also observed in prion diseases. Aggregation of PRNP upregulates ER chaperones and activates EIF2AK3-EIF2S1 signaling, resulting in synaptic failure and activation of a caspase cascade, which can be rescued by the EIF2AK3 inhibitor GSK2606414 but not the PPP1R15A inhibitor salubrinal. Overexpression of UPR mediators such as ATF6, ATF4 and XBP1 reduces PRNP aggregation in vitro, but it is not fully extrapolated in XBP1 conditional knockout mice. RTN3 activated by ER stress restrains autophagy by prohibiting dissociation of BCL2 and BECN1. Autophagic activities can be enhanced by overexpression of SIRT1 and autophagic inducers, and can be inhibited by either genetic silencing of ATG5 or in the presence of the autophagic inhibitor 3-MA.

Figure 6.

ER stress and autophagy in PD. Phosphorylation of EIF2AK3 can be induced by both SNCA and 6-OHDA. Although phosphorylated EIF2S1 is seen in PD brain but not in the α-synucleinopathy mouse model, EIF2S1-ATF4 signaling upregulates PARK2. Interaction of PARK2 and BECN1 enhances autophagic clearance of SNCA. Moreover, exogenous XBP1s and XBP1 rescue MPP⁺/MPTP-mediated dopaminergic neuron degeneration.

Figure 7.

ER stress and autophagy in ALS. Different mutations such as those in SOD1, TARDBP and FUS are all able to induce neuronal apoptosis through activation of DDIT3. Both TARDBP and FUS can be included in stress granules in the cytoplasm. Phosphorylation of EIF2S1 mediated by TARDBP and mSOD1 (mutant SOD1) facilitates stress granules formation. Interestingly, either FUS or mSOD1 increases expression of XBP1s but activated XBP1s inhibits autophagic clearance of mSOD1. Moreover, mOPTN (mutant OPTN) also hampers autophagy by inhibiting fusion of autophagosomes with lysosomes. Enhanced autophagic activity induced by autophagic inducers leads to clearance of FUS and TARDBP. Interestingly, SQSTM1 plays a crucial role in packaging TARDBP into autophagosomes.

Figure 8.

ER stress and autophagy in HAND. Although no direct evidence is found between UPR and autophagy in HAND, it has been suggested that HIV viral proteins induce ER stress and inhibit autophagic clearance. Both gp120 and Tat induce calcium-dependent ER stress, and Tat increases expression of major UPR mediators such as HSPA5, ATF6, phosphorylated EIF2AK3 and EIF2S1. Viral proteins such as Nef and gp120 hamper autophagosome formation initiated by BECN1 while Tat hinders the fusion of lysosomes with autophagosomes. BBB, blood-brain barrier.