Hereditary spastic paraplegias proteome: common pathways and pathogenetic mechanisms

ABSTRACT

Introduction

Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness of the lower limbs. These conditions are caused by lesions in the neuronal pyramidal tract and exhibit clinical and genetic variability. Ongoing research focuses on understanding the underlying mechanisms of HSP onset, which ultimately lead to neuronal degeneration. Key molecular mechanisms involved include axonal transport, cytoskeleton dynamics, myelination abnormalities, membrane trafficking, organelle morphogenesis, ER homeostasis, mitochondrial dysfunction, and autophagy deregulation.

Areas covered

This review aims to provide an overview of the shared pathogenetic mechanisms in various forms of HSPs. By examining disease-causing gene products and their associated functional pathways, this understanding could lead to the discovery of new therapeutic targets and the development of treatments to modify the progression of the disease.

Expert opinion

Investigating gene functionality is crucial for identifying shared pathogenetic pathways underlying different HSP subtypes. Categorizing protein function and identifying pathways aids in finding biomarkers, predicting early onset, and guiding treatment for a better quality of life. Targeting shared mechanisms enables efficient and cost-effective therapies. Prospects involve identifying new disease-causing genes, refining molecular processes, and implementing findings in diagnosis, key for advancing HSP understanding and developing effective treatments.

KEYWORDS:

• Hereditary spastic paraplegia
• common pathogenetic pathways
• axon trafficking
• ER morphology and trafficking
• myelination
• lipid metabolism
• mitochondria
• target therapies

Article highlights

• Hereditary spastic paraplegias (HSPs) are inherited neurodegenerative disorders characterized by progressive spasticity and weakness of the lower limbs.

• HSPs exhibit clinical and genetic variability, with over 87 forms associated with at least 73 different causative genes.

• HSPs can be inherited through autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance patterns.

• Research is focused on understanding the shared pathogenetic mechanisms of HSPs, including axonal transport, cytoskeleton dynamics, myelination abnormalities, and mitochondrial dysfunction, which lead to neuronal degeneration.

• The aim is to identify therapeutic targets and develop disease-modifying treatments for HSPs and potentially other neurological diseases.

13. Glossary

HSP: hereditary spastic paraplegia; AD: autosomal dominant; AR: autosomal recessive; XL: X-linked; MT: microtubule; AAA: ATPase associated with various cellular activities; ATP: Adenosine Triphosphate; MTBD: microtubule-binding domain; KIF5A: Kinesin family member 5A; KIF1A: Kinesin Family member 1A; KLC2: Kinesin light chain 2; KIF1C: Kinesin family member 1C; ER: Endoplasmic Reticulum; ATL1: Atlastin-1; ATL2: Atlastin-2; ATL3: Atlastin-3; ERGIC: ER to Golgi Intermediate Compartment; CNS: Central Nervous System; RTNs: Reticulons; RHD: Reticulon Homology Domain; RTN2: Reticulon-2; REEP1: Receptor Expression-Enhancing Protein 1; REEP2: Receptor Expression-Enhancing Protein 2; APH: Amphipathic Helix; Rab3GAP2: Rab3 GTPase-activating Protein Non-Catalytic Subunit; FFAT: Two Phenylalanines in an Acidic Tract; ARL6IP1: ADP-Ribosylation Factor-like 6 Interacting Protein 1; MAMs: Mitochondria-associated Endoplasmic Reticulum Membranes; ERES: ER-Exit Sites; TFG: TRK-fused gene protein; TECPR2: Tectonin Beta-Propeller Repeat Containing 2 protein; ATG8: Autophagy-related protein 8; GPI: Glycosylphosphatidylinositol; GPI-APs: Glycosylphosphatidylinositol-anchored Proteins; PGAP1: post-GPI Attachment to Proteins 1; ERAD: ER-Associated Degradation; ERLIN-1: Endoplasmic Reticulum Lipid Raft Associated 1; ERLIN-2: Endoplasmic Reticulum Lipid Raft Associated 2; SPFH: Stomatin-Prohibitn-Flotillin-HflC/K; RNF170: Ring Finger protein 170; IP3R: Inositol 1,4,5-Trisphosphate Receptor; EE: Early Endosome; MVB: Multivesicular Body; TGN: Trans-Golgi Network; WASH: Wiskott–Aldrich Syndrome Protein and SCAR Homolog; WASHC1: Wash Complex Subunit 1; FAM21: Family with Sequence Similarity 21; ARP2/3: Actin-Related Protein 2/3; CAV1: Caveolin 1; ESCRT: Endosomal Sorting Complexes Required for Transport; VPS37A: Vacuolar Protein Porting-associated Protein 37A; UBAP1: Ubiquitin-associated Protein 1; SOUBA: Solenoid of Overlapping Ubiquitin-associated domains; CHMP1B: Charged Multivesicular Body protein 1B; MIT: Microtubule Interacting and Trafficking; USP8: Ubiquitin Specific Peptidase 8; WDR48: WD Repeat Containing Protein 48; AP: Adaptor Protein; BMP: Bone Morphogenic Protein; EGFR: Epidermal Growth Factor Receptor; TGFβ: Transforming Growth Factor Beta; BMPRII: type II BMP Receptor; BMPRI: type I BMP Receptor; PAS: phagophore assembly site; ATG9A: Autophagy-related Protein 9A; CHMP2A: Charged Multivesicular Body proteins 2A; HOPS: Homotypic Fusion and Vacuole Protein Sorting; LIR: LC3-interacting region; ATP13A2: ATPase Cation Transporting 13A2; ALR: autophagic lysosome reformation; L1CAM: L1 Cell Adhesion Molecule; CAM: Cell Adhesion Molecules; PLP1: Proteolipid Protein 1; CX47: Connexin 47; MAG: Myelin-associated Glycoprotein; FA2H: Fatty Acid 2-Hydroxylase; AMPD2: Adenosine Monophosphate Deaminase 2; AMP: Adenosine Monophosphate; IMP: Inosine Monophosphate; ENTPD1: Ectonucleoside Triphosphate Diphosphohydrolase 1; P5CS: Delta-1-Pyrroline-5-Carboxylate Synthetase; NADPH: Nicotinamide Adenine Dinucleotide Phosphate; G5K: Glutamate 5-Kinase; G5PR: Glutamyl-5-Phosphate Reductase; MARS1: Methionyl-tRNA Synthetase 1; ARS: Aminoacyl tRNA Synthetases; LDs: lipid droplets; DDHD2: DDHD Domain-containing Protein 2; B4GALNT1: Beta −1,4 N-acetylgalactosaminyltransferase 1; ROS: Reactive Oxygen Species; AFG3L2: ATPase Family Gene 3-like 2; HSP60: Heat Shock Protein 60; mtPheRS: mitochondrial Phenylalanyl tRNA Synthetase; MTRFR: Mitochondrial translation release factor in rescue; HPDL: 4-hydroxyphenylpyruvate dioxygenase-like protein; FDA: Food and Drug Administration; RM: Rapamycin; MB: Methylene Blue; NAC: N-acetyl cysteine; GA: Guanabenz; SAL: Salubrinal; NAR: Naringenin.

Acknowledgments

C Martinello and E Panza equally contributed to the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Italian Ministry of Health [Grant no. RF19.12 to A.O.] and the Department of Medicine and Surgery of the University of Perugia [Fondo Ricerca di Base, Grants no. DSCH_BASE19_ORLACCHIO and RICERCABASE_2020_ORLACCHIO to A.O].