Editing Lysosome (section)

==Clinical significance==

Lysosomal storage disorders are a group of metabolic disorders that stem from inherited genetic mutations that disrupt normal lysosomal function and homeostasis.<ref name="Samie Xu Lysosomal exocytosis"/><ref name="Platt Lysosomal storage disorders">{{cite journal |last1=Platt |first1=Frances M. |last2=Boland |first2=Barry |last3=van der Spoel |first3=Aarnoud C. |title=Lysosomal storage disorders: The cellular impact of lysosomal dysfunction |journal=Journal of Cell Biology |date=26 November 2012 |volume=199 |issue=5 |pages=723–734 |doi=10.1083/jcb.201208152 |pmc=3514785 |pmid=23185029 }}</ref> Most frequently, the mutations are located in the acidic hydrolases but can also be found in non-enzymatic lysosomal proteins (soluble and membrane-bound) and non-lysosomal factors controlling lysosomal function.<ref>{{Cite journal |last1=Carmona-Gutierrez |first1=Didac |last2=Hughes |first2=Adam L. |last3=Madeo |first3=Frank |last4=Ruckenstuhl |first4=Christoph |date=2016-12-01 |title=The crucial impact of lysosomes in aging and longevity |journal=Ageing Research Reviews |volume=32 |pages=2–12 |doi=10.1016/j.arr.2016.04.009 |pmc=5081277 |pmid=27125853}}</ref> This leads to defective degradation, and therefore induces abnormal accumulations of un- or partially digested macromolecules within lysosomes. Lysosomal dysfunction also affect transport across the lysosomal membrane, vesicle trafficking, lysosome reformation and autophagy.<ref>{{Cite journal |last1=Bouhamdani |first1=Nadia |last2=Comeau |first2=Dominique |last3=Turcotte |first3=Sandra |date=2021-12-15 |title=A Compendium of Information on the Lysosome |journal=Frontiers in Cell and Developmental Biology |language=English |volume=9 |doi=10.3389/fcell.2021.798262 |doi-access=free |pmid=34977038 |pmc=8714965 }}</ref><ref name="Samie Xu Lysosomal exocytosis"/>

The stress of accumulated lysosomal substrates can lead to lysosomal membrane permeabilization, allowing hydrolytic enzymes to leak into the cytosol and initiate cell death. This cell loss particularly affects post-mitotic tissues such as the brain, liver, eyes, muscles, and spleen—resulting in the hallmark symptoms of lysosomal storage disorders, including neurodegeneration, cognitive impairment, and motor dysfunction.<ref name="Platt Lysosomal storage disorders"/><ref>{{Cite journal |last1=Carmona-Gutierrez |first1=Didac |last2=Hughes |first2=Adam L. |last3=Madeo |first3=Frank |last4=Ruckenstuhl |first4=Christoph |date=2016-12-01 |title=The crucial impact of lysosomes in aging and longevity |journal=Ageing Research Reviews |volume=32 |pages=2–12 |doi=10.1016/j.arr.2016.04.009 |pmc=5081277 |pmid=27125853}}</ref>

The age of onset and the specific symptoms in lysosomal storage disorders differ depending on the severity of the mutations, the cell types affected and what substrates accumulate. However, the clinical presentation is typically a neurodegenerative disease at childhood, with more variations presenting themselves in adulthood. In most cases, the central nervous system (CNS) is affected, causing the brain to experience global neurodegeneration, inflammation, activation of the innate immune system and astrogliosis.<ref name="Platt Lysosomal storage disorders"/>

Several therapeutic strategies have been developed to address lysosomal storage disorders. These include substrate reduction therapy, bone marrow transplantation, gene therapy, and enzyme replacement therapy. Currently, enzyme replacement therapy and substrate reduction are the most widely used. However, despite these advancements most lysosomal storage disorders still lack effective treatments as the existing ones often are limited by poor efficacy and are typically disease specific.<ref name="Platt Lysosomal storage disorders"/>

===Lysosomotropism===

Lysosomotropism refers to the tendency of lipophilic weak bases to accumulate in acidic organelles like lysosomes. While neutral forms of these compounds cross membranes easily, their protonated (charged) forms become trapped inside lysosomes, leading to concentrations up to 1000 times higher than outside the cell.<ref>{{cite journal |last1=de Duve |first1=Christian |last2=de Barsy |first2=Thierry |last3=Poole |first3=Brian |last4=Trouet |first4=André |last5=Tulkens |first5=Paul |last6=van Hoof |first6=François |title=Lysosomotropic agents |journal=Biochemical Pharmacology |date=September 1974 |volume=23 |issue=18 |pages=2495–2531 |doi=10.1016/0006-2952(74)90174-9 |pmid=4606365 }}</ref><ref>{{cite book |doi=10.1016/s0091-679x(08)61717-3 |chapter=Chapter 12 Lysosomal Proton Pump Activity: Supravital Cell Staining with Acridine Orange Differentiates Leukocyte Subpopulations |title=Flow Cytometry Second Edition, Part A |series=Methods in Cell Biology |date=1994 |last1=Traganos |first1=Frank |last2=Darzynkiewicz |first2=Zbigniew |volume=41 |pages=185–194 |pmid=7532261 |isbn=978-0-12-564142-5 }}</ref> This “acid trapping” or “proton pump” effect can be predicted using mathematical models.<ref>{{cite journal |last1=Trapp |first1=Stefan |last2=Rosania |first2=Gus R. |last3=Horobin |first3=Richard W. |last4=Kornhuber |first4=Johannes |title=Quantitative modeling of selective lysosomal targeting for drug design |journal=European Biophysics Journal |date=October 2008 |volume=37 |issue=8 |pages=1317–1328 |doi=10.1007/s00249-008-0338-4 |pmc=2711917 |pmid=18504571 }}</ref>

Many approved drugs, including haloperidol,<ref>{{cite journal |last1=Kornhuber |first1=Johannes |last2=Schultz |first2=Andreas |last3=Wiltfang |first3=Jens |last4=Meineke |first4=Ingolf |last5=Gleiter |first5=Christoph H. |last6=Zöchling |first6=Robert |last7=Boissl |first7=Karl-Werner |last8=Leblhuber |first8=Friedrich |last9=Riederer |first9=Peter |title=Persistence of Haloperidol in Human Brain Tissue |journal=American Journal of Psychiatry |date=June 1999 |volume=156 |issue=6 |pages=885–890 |doi=10.1176/ajp.156.6.885 |pmid=10360127 }}</ref> levomepromazine,<ref>{{cite journal |last1=Kornhuber |first1=J. |last2=Weigmann |first2=H. |last3=Röhrich |first3=J. |last4=Wiltfang |first4=J. |last5=Bleich |first5=S. |last6=Meineke |first6=I. |last7=Zöchling |first7=R. |last8=Härtter |first8=S. |last9=Riederer |first9=P. |last10=Hiemke |first10=C. |title=Region specific distribution of levomepromazine in the human brain |journal=Journal of Neural Transmission |date=March 2006 |volume=113 |issue=3 |pages=387–397 |doi=10.1007/s00702-005-0331-3 |pmid=15997416 }}</ref> and amantadine,<ref>{{cite journal |last1=Kornhuber |first1=J. |last2=Quack |first2=G. |last3=Danysz |first3=W. |last4=Jellinger |first4=K. |last5=Danielczyk |first5=W. |last6=Gsell |first6=W. |last7=Riederer |first7=P. |title=Therapeutic brain concentration of the NMDA receptor antagonist amantadine |journal=Neuropharmacology |date=July 1995 |volume=34 |issue=7 |pages=713–721 |doi=10.1016/0028-3908(95)00056-C |pmid=8532138 }}</ref> exhibit lysosomotropic behavior. This helps explain their high tissue-to-blood concentration ratios and prolonged tissue retention, though fat solubility also contributes.

Some lysosomotropic drugs can interfere with lysosomal enzymes like acid sphingomyelinase.<ref>{{cite journal |last1=Kornhuber |first1=Johannes |last2=Tripal |first2=Philipp |last3=Reichel |first3=Martin |last4=Terfloth |first4=Lothar |last5=Bleich |first5=Stefan |last6=Wiltfang |first6=Jens |last7=Gulbins |first7=Erich |title=Identification of New Functional Inhibitors of Acid Sphingomyelinase Using a Structure−Property−Activity Relation Model |journal=Journal of Medicinal Chemistry |date=2008 |volume=51 |issue=2 |pages=219–237 |doi=10.1021/jm070524a |pmid=18027916 }}</ref><ref>{{Cite journal |last1=Kornhuber |first1=Johannes |last2=Muehlbacher |first2=Markus |last3=Trapp |first3=Stefan |last4=Pechmann |first4=Stefanie |last5=Friedl |first5=Astrid |last6=Reichel |first6=Martin |last7=Mühle |first7=Christiane |last8=Terfloth |first8=Lothar |last9=Groemer |first9=Teja W. |last10=Spitzer |first10=Gudrun M. |last11=Liedl |first11=Klaus R. |last12=Gulbins |first12=Erich |last13=Tripal |first13=Philipp |date=2011-08-31 |title=Identification of Novel Functional Inhibitors of Acid Sphingomyelinase |journal=PLOS ONE |volume=6 |issue=8 |pages=e23852 |doi=10.1371/journal.pone.0023852 |doi-access=free |pmc=3166082 |pmid=21909365 |bibcode=2011PLoSO...623852K }}</ref> Ambroxol, a mucolytic, promotes lysosomal exocytosis by neutralizing lysosomal pH and releasing stored calcium.<ref>{{cite journal |last1=Marshall |first1=Kirsty |last2=Easton |first2=Chris |title=The role of asset-based approaches in community nursing |journal=Primary Health Care |date=25 July 2018 |volume=28 |issue=5 |pages=35–38 |doi=10.7748/phc.2018.e1339 }}</ref> This action may underlie its observed benefits in diseases linked to lysosomal dysfunction, including Parkinson's disease and lysosomal storage disorders.<ref>{{cite journal |last1=Albin |first1=Roger L. |last2=Dauer |first2=William T. |title=Magic shotgun for Parkinson's disease? |journal=Brain |date=May 2014 |volume=137 |issue=5 |pages=1274–1275 |doi=10.1093/brain/awu076 |pmid=24771397 }}</ref><ref>{{Cite journal |last1=McNeill |first1=Alisdair |last2=Magalhaes |first2=Joana |last3=Shen |first3=Chengguo |last4=Chau |first4=Kai-Yin |last5=Hughes |first5=Derralyn |last6=Mehta |first6=Atul |last7=Foltynie |first7=Tom |last8=Cooper |first8=J. Mark |last9=Abramov |first9=Andrey Y. |last10=Gegg |first10=Matthew |last11=Schapira |first11=Anthony H. V. |date=May 2014 |title=Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells |journal=Brain: A Journal of Neurology |volume=137 |issue=Pt 5 |pages=1481–1495 |doi=10.1093/brain/awu020 |pmc=3999713 |pmid=24574503 }}</ref>

=== Systemic lupus erythematosus (Lupus) ===
Systemic lupus erythematosus (SLE) otherwise known as Lupus is an autoimmune disease where the immune system attacks healthy cells.<ref>{{Cite web |date=2025-04-03 |title=Lupus: Symptoms & Treatment |url=https://my.clevelandclinic.org/health/diseases/4875-lupus |access-date=2025-04-09 |archive-url=http://web.archive.org/web/20250403230150/https://my.clevelandclinic.org/health/diseases/4875-lupus |archive-date=3 April 2025 }}</ref> Lupus is prominent in systemic lupus erythematosus preventing macrophages and monocytes from degrading neutrophil extracellular traps<ref>{{Cite journal |last1=Hakkim |first1=Abdul |last2=Fürnrohr |first2=Barbara G. |last3=Amann |first3=Kerstin |last4=Laube |first4=Britta |last5=Abed |first5=Ulrike Abu |last6=Brinkmann |first6=Volker |last7=Herrmann |first7=Martin |last8=Voll |first8=Reinhard E. |last9=Zychlinsky |first9=Arturo |date=2010-05-25 |title=Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis |journal=Proceedings of the National Academy of Sciences |volume=107 |issue=21 |pages=9813–9818 |doi=10.1073/pnas.0909927107 |doi-access=free |pmc=2906830 |pmid=20439745|bibcode=2010PNAS..107.9813H }}</ref> and immune complexes.<ref name=":3">{{Cite journal |last1=Monteith |first1=Andrew J. |last2=Kang |first2=SunAh |last3=Scott |first3=Eric |last4=Hillman |first4=Kai |last5=Rajfur |first5=Zenon |last6=Jacobson |first6=Ken |last7=Costello |first7=M. Joseph |last8=Vilen |first8=Barbara J. |date=2016-04-12 |title=Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus |journal=Proceedings of the National Academy of Sciences |volume=113 |issue=15 |pages=E2142–E2151 |doi=10.1073/pnas.1513943113 |doi-access=free |pmc=4839468 |pmid=27035940|bibcode=2016PNAS..113E2142M }}</ref><ref>{{cite journal |last1=Kavai |first1=Maria |last2=Szegedi |first2=Gyula |title=Immune complex clearance by monocytes and macrophages in systemic lupus erythematosus |journal=Autoimmunity Reviews |date=August 2007 |volume=6 |issue=7 |pages=497–502 |doi=10.1016/j.autrev.2007.01.017 |pmid=17643939 }}</ref><ref>{{cite journal |last1=KáVai |first1=M. |last2=Csipö |first2=I. |last3=Sonkoly |first3=J. |last4=Csongor |first4=J. |last5=Szegedi |first5=G. Y. |title=Defective Immune Complex Degradation by Monocytes in Patients with Systemic Lupus Erythematosus. |journal=Scandinavian Journal of Immunology |date=November 1986 |volume=24 |issue=5 |pages=527–532 |doi=10.1111/j.1365-3083.1986.tb02167.x |pmid=3787186 }}</ref> The failure to degrade internalized immune complexes rises from irregularly extended activity of mTORC2, which impairs lysosome acidification.<ref>{{Cite journal |last1=Monteith |first1=Andrew J |last2=Vincent |first2=Heather A |last3=Kang |first3=SunAh |last4=Li |first4=Patrick |last5=Claiborne |first5=Tauris M |last6=Rajfur |first6=Zenon |last7=Jacobson |first7=Ken |last8=Moorman |first8=Nathaniel J |last9=Vilen |first9=Barbara J |date=2018-07-01 |title=mTORC2 Activity Disrupts Lysosome Acidification in Systemic Lupus Erythematosus by Impairing Caspase-1 Cleavage of Rab39a |journal=The Journal of Immunology |volume=201 |issue=2 |pages=371–382 |doi=10.4049/jimmunol.1701712 |pmc=6039264 |pmid=29866702}}</ref> As a result, immune complexes in the lysosome recycle to the surface of macrophages causing an accumulation of DNA fragments and nuclear complexes which triggers an immune response from the body which is leads to the multiple lupus-associated pathologies.<ref name=":3" /><ref>{{Cite journal |last1=Kang |first1=SunAh |last2=Rogers |first2=Jennifer L |last3=Monteith |first3=Andrew J |last4=Jiang |first4=Chuancang |last5=Schmitz |first5=John |last6=Clarke |first6=Stephen H |last7=Tarrant |first7=Teresa K |last8=Truong |first8=Young K |last9=Diaz |first9=Marilyn |last10=Fedoriw |first10=Yuri |last11=Vilen |first11=Barbara J |date=2016-05-01 |title=Apoptotic Debris Accumulates on Hematopoietic Cells and Promotes Disease in Murine and Human Systemic Lupus Erythematosus |journal=The Journal of Immunology |volume=196 |issue=10 |pages=4030–4039 |doi=10.4049/jimmunol.1500418 |pmc=4868781 |pmid=27059595}}</ref><ref>{{Cite journal |last1=Kang |first1=SunAh |last2=Fedoriw |first2=Yuri |last3=Brenneman |first3=Ethan K |last4=Truong |first4=Young K |last5=Kikly |first5=Kristine |last6=Vilen |first6=Barbara J |date=2017-04-01 |title=BAFF Induces Tertiary Lymphoid Structures and Positions T Cells within the Glomeruli during Lupus Nephritis |journal=The Journal of Immunology |volume=198 |issue=7 |pages=2602–2611 |doi=10.4049/jimmunol.1600281 |pmc=5360485 |pmid=28235864}}</ref>