Cell Biology of Human Diseases

Alzheimer’s Disease (AD)

Processing of Amyloid Precursor ProteinCleavage by α-secretase interior to the β-amyloid peptide (Aβ) sequence initiates nonamyloidogenic processing. A large amyloid precursor protein (sAPPα) ectodomain is released, leaving behind an 83-residue carboxy-terminal fragment. C83 is then digested by γ-secretase, liberating extracellular p3 and the amyloid intracellular domain (AICD). Amyloidogenic processing is initiated by β-secretase beta-site amyloid precursor protein–cleaving enzyme 1 (BACE-1), releasing a shortened sAPPα. The retained C99 is also a γ-secretase substrate, generating Aβ and AICD. γ-Secretase cleavage occurs within the cell membrane in a unique process termed “regulated intramembranous proteolysis.” sAPPα and sAPPβ are secreted APP fragments after α-secretase and β-secretase cleavages, respectively. AICD is a short tail (approximately 50 amino acids) that is released into the cytoplasm after progressive ε-to-γ cleavages by γ-secretase. AICD is targeted to the nucleus, signaling transcription activation. Lipid rafts are tightly packed membrane micro-environments enriched in sphingomylelin, cholesterol, and glycophosphatidylinositol (GPI)–anchored proteins. Soluble Aβ is prone to aggregation.

Two Mechanisms of SIRT1 Protection against Alzheimer’s Disease.SIRT1 directs cleavage of amyloid precursor protein (APP) away from production of the toxic β-amyloid peptide (Aβ) by activating the gene encoding α-secretase. It also deacetylates tau for ubiquitination and proteasomal destruction, thereby reducing tangles. Fragments sAPPβ and C99 are produced by β-secretase cleavage of APP, and fragments sAPPα and C83 are produced by α-secretase cleavage of APP. AICD is the APP intracellular domain produced by γ-secretase cleavage of C99 and C83.N Engl J Med 2011;364:2235-44.

Malaria

The Life Cycle of P. falciparum in the Human Hostand the Anopheles Mosquito Vector

The Plasmodium-infected mosquito injects sporozoite forms into the human host, and these migrate to the liver, where they can pass through Kuppfer cells and invade hepatocytes within which they develop into liver merozoites. These merozoites are released into the bloodstream, where they invade erythrocytes. They develop through ring, trophozoite, and schizont stages, replicating to produce from16 to 32 daughter merozoites that are released during egress. The free merozoite is then able to invade other erythrocytes to continue the asexual blood-stage life cycle. All clinical symptoms arise during this asexual blood cycle. In the blood, some intraerythrocytic stages develop into male or female gametocytes, the sexual forms of the parasite.These are taken up by the mosquito during feeding, develop into gametes in the insect gut, and fuse to form zygotes. The zygote develops to form an invasive ookinete, which traverses the midgut and transforms into an oocyst from which sporozoites are released that migrate to the salivary glands for injection into a human host during the next blood meal.

Diagram of a Merozoite, Highlighting Major Organelles and Cellular Structures

Merozoite Invasion of ErythrocytesInvasion involves an initial ‘‘long-distance’’ recognition of surface receptors (A) followed by a reorientation process whereby these low affinity contacts are maintained. Once the apical end is adjacent to the erythrocyte (B), a tight junction is formed involving high-affinity ligand receptor interactions. This tight junction then moves from the apical to posterior pole (C and D) powered by the parasite’s actin-myosin motor. The surface coat is shed at the moving junction by a serine protease, or ‘‘sheddase.’’ Upon reaching the posterior pole, the adhesive proteins at the junction are also proteolytically removed (E), this time by a resident protease, most likely a rhomboid, in a process that facilitates resealing of the membrane. By this process, the parasite does not actually penetrate the membrane but invades in a manner that creates a parasitophorous vacuole.

Egress of Plasmodium Merozoites(A) Mature schizont-stage parasites contain 16 or so fully formed merozoites.(B) The parasitophorous-vacuole membrane ruptures first, apparently due to the action of proteases, and the merozoites are free within the intact erythrocyte.(C and D) Swelling of the erythrocyte and degradation of the cytoskeleton (C) leads to an explosive lysis and scattering of the free merozoites and vesiculation of the host-cell membrane (D).

Lysosomal Storage Disorders

Extraordinary Measures is a 2010 medical drama film starring Brendan Fraser, Harrison Ford, and Keri Russell. It is distributed by CBS Films and was released on January 22, 2010. It is about parents who form a biotechnology company to develop a drug to save the lives of their children, who have a life-threatening disease. The film is based on the true story of John and Aileen Crowley, whose children have Pompe's disease.

Cancer

The Hallmarks of CancerThis illustration encompasses the six hallmark capabilities originally proposed in 2000. The past decade has witnessed remarkable progress toward understanding the mechanistic underpinnings of each hallmark.

Intracellular Signaling Networks Regulate the Operations of the Cancer Cell

Emerging Hallmarks and Enabling CharacteristicsAn increasing body of research suggests that two additional hallmarks of cancer are involved in the pathogenesis of some and perhaps all cancers. One involves the capability to modify, or reprogram, cellular metabolism in order to most effectively support neoplastic proliferation. The second allows cancer cells to evade immunological destruction, in particular by T and B lymphocytes, macrophages, and natural killer cells. Because neither capability is yet generalized and fully validated, they are labeled as emerging hallmarks. Additionally, two consequential characteristics of neoplasia facilitate acquisition of both core and emerging hallmarks. Genomic instability and thus mutability endow cancer cells with genetic alterations that drive tumor progression. Inflammation by innate immune cells designed to fight infections and heal wounds can instead result in their inadvertent support of multiple hallmark capabilities, thereby manifesting the now widely appreciated tumor-promoting consequences of inflammatory responses.

Therapeutic Targeting of the Hallmarks of Cancer