Lysosomes as a therapeutic target

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Lysosomes are membrane-bound organelles with roles in processes involved in degrading and recycling cellular waste, cellular signalling and energy metabolism. Defects in genes encoding lysosomal proteins cause lysosomal storage disorders, in which enzyme replacement therapy has proved successful. Growing evidence also implicates roles for lysosomal dysfunction in more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. With a focus on lysosomal dysfunction in autoimmune disorders and neurodegenerative diseases — including lupus, rheumatoid arthritis, multiple sclerosis, Alzheimer disease and Parkinson disease — this Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs.

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Fig. 1: The central position of lysosomes at the crossroads of major autophagic pathways.
Fig. 2: Lysosomal molecular sites and processes as possible targets for therapeutic strategies.
Fig. 3: Structures of selected pharmacological molecules designed to correct lysosomal dysregulation in disease.


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The authors apologize to all those whose work is not cited due to space limitations. They gratefully acknowledge Hélène Jeltsch-David for critically reading the manuscript. This research was funded by the French Centre National de la Recherche Scientifique, Région Alsace, the Laboratory of Excellence Medalis (ANR-10-LABX-0034), Initiative of Excellence (IdEx), Strasbourg University, and ImmuPharma France. S.M. is grateful to the University of Strasbourg Institute for Advanced Study (USIAS) for funding F.W., and acknowledges the support of the TRANSAUTOPHAGY COST Action (CA15138), the Club francophone de l’autophagie (CFATG) and the European Regional Development Fund of the European Union in the framework of the INTERREG V Upper Rhine programme.

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All authors made substantial, direct and intellectual contribution to the work and approved it for publication.

Correspondence to Sylviane Muller.

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Competing interests

S.M. discloses the following conflicts of interest: research funding (paid to institution) and a past consultant for ImmuPharma; co-inventor of CNRS-ImmuPharma patents on P140 peptide; owns ImmuPharma shares. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. S.R.B. and F.W. declare no competing interests.

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A vesicle-mediated process by which cells engulf membrane and extracellular materials. Several endocytic pathways — phagocytosis, pinocytosis and receptor-mediated endocytosis — utilize different mechanisms to internalize material. Clathrin-mediated endocytosis is the major endocytic pathway in mammalian cells.


An endocytic process by which certain cells called phagocytes (for example, macrophages) internalize large particles (>0.5 µm) such as bacteria, other microorganisms, foreign particles or aged red blood cells, for example, to form a phagosome.


A vital, finely-regulated and evolutionarily-conserved intracellular pathway that continuously degrades, recycles and clears unnecessary or dysfunctional cellular components. Autophagy is crucial for cell adaptation to the environment and to maintain cell homeostasis, especially under stress conditions.

Golgi apparatus

Cytosolic apparatus, meant for the regulation of proteins (modification, storing and transportation) and some forms of lipids to the other cytosolic compartments via the trans-Golgi network or outside the cell.

Lysosomal exocytosis

A process of the secretory pathway in which lysosomes are fused with the plasma membrane and empty their contents outside the cell. This process plays an important role in plasma membrane repair, bone resorption, immune response and elimination of pathogenic stores (mainly in lysosomal storage disorders).

Lysosomal storage disorders

(LSDs). A group of heterogeneous disorders caused by defects in the lysosomal enzymes leading to the accumulation of unmodified or unprocessed components in the lysosomes, which ultimately influence other vital pathways in the cells. LSDs implicate various vital systems of the human body including the skeleton, brain, skin, heart and central nervous system, which are connected with different metabolic pathways.

Rheumatoid arthritis

(RA). An autoimmune disease involving inflammation and degeneration of the joints that affects an estimated 1% of the population, making it the most common inflammatory arthritis.

Multiple sclerosis

(MS). A demyelinating disease in which the myelin sheaths wrapped around nerve fibres in the central nervous system are progressively destroyed by immune cells and possibly also by autoantibodies.

Parkinson disease

(PD). A neurodegenerative disorder with symptoms including slowness of movement and a loss of fine motor control, owing to the degeneration of dopamine-producing neurons in the substantia nigra.

Chaperone-mediated autophagy

(CMA). A selective autophagy pathway in which proteins that contain a signal KFERQ-like sequence are targeted by HSAP8/HSC70 chaperones and translocated into lysosomes via LAMP2A.

Transcription factor EB

(TFEB). A protein that plays a pivotal role in the regulation of basic cellular processes, such as lysosomal biogenesis and autophagy. It controls lysosomal function via the coordinated lysosomal expression and regulation (CLEAR) gene network (including genes coding for hydrolases, lysosomal membrane proteins and the proton pump v-ATPase complex), and additional lysosome-related processes such as autophagy, endocytosis and exocytosis.


A finely-regulated process during which the cell forms a double-membrane sequestering compartment named the phagophore, which matures into the autophagosome.


A double membrane-bound vesicle, which encloses cellular constituents and fuses with lysosomes to form phagolysosomes where the engulfed material is digested or degraded and either released extracellularly via exocytosis or released intracellularly to undergo further processing.


A key process that selectively disrupts damaged mitochondria by autolysosomal degradation, preventing excessive reactive oxygen species and activation of cell death.


(HTT). Discovered in 1993, HTT is a protein of 348 kDa that is widely expressed within the central nervous system. Its structure has been elucidated recently by cryo-electron microscopy. The protein is essential for embryonic development and neurogenesis. It is involved in transcription, vesicle transport, protein trafficking, endocytosis and autophagy.

Systemic lupus erythematosus

(SLE). A chronic, relapsing–remitting autoinflammatory syndrome that has multiple and heterogeneous symptoms, including arthralgia, swollen joints, fever, fatigue, chest pain, kidney inflammation, cardiovascular disease and neuropsychiatric complications. Its aetiology is mostly unknown.

Sjögren’s syndrome

(SjS). A multifactorial systemic autoimmune disorder characterized by lymphocytic infiltrates in exocrine organs. Symptoms include dry eyes, dry mouth and parotid enlargement, and serious complications include fatigue, chronic pain, neuropathies and lymphomas.

Myasthenia gravis

Caused by antibodies targeting the muscle acetylcholine receptor or other neuromuscular junction proteins such as muscle-specific kinase. These antibodies compromise communication between nerves and muscles, leading to muscular weakness and fatigue.

Chronic inflammatory demyelinating polyneuropathy

(CIDP). A progressive autoimmune disorder in which peripheral nerves (roots and trunks) and brachial plexuses are damaged owing to demyelination. It causes muscle weakness, sensory loss and reduced reflexes.

Neuromyelitis optica

Also known as Devic’s syndrome, this disease is characterized by an inflammation and demyelination of the optic nerve (optic neuritis) and the spinal cord (myelitis). Antibodies reacting with aquaporin-4 water channels in the brains of patients are implicated in neuromyelitis optica.

Amyotrophic lateral sclerosis

(ALS). Also known as motor neuron disease, this disease generally starts with muscle twitching and weakness in a limb, or slurred speech. It can affect control of the muscles needed to move, speak, eat and breathe, and can be fatal.


A major microtubule-associated protein of a mature neuron. Hyperphosphorylated tau accumulates with ubiquitin in ageing neurons as the neurofibrillary tangles that were identified in numerous neurodegenerative diseases called tauopathies that include Alzheimer disease.

Fabry disease

(FD). A progressive, X-linked inherited, multisystemic lysosomal storage disorder caused by GLA mutations, resulting in α-galactosidase deficiency and accumulation of lysosomal substrate.

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